Novel glucokinase activators and methods of using same

ABSTRACT

Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure 
     
       
         
         
             
             
         
       
     
     wherein 
     
       
         
         
             
             
         
       
     
     is a heteroaryl ring;
         R 4  is —(CH 2 ) n —Z—(CH 2 ) m PO(OR 7 )(OR 8 ),
           —(CH 2 ) n Z—(CH 2 ) m —PO(OR 7 )R 9 ,   —(CH 2 ) n —Z—(CH 2 ) m —OPO(OR 7 )R 9 ,   —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or   —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 );   
           R 5  and R 6  are independently selected from H, alkyl and halogen;   Y is R 7 (CH 2 ) s  or is absent; and   X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein;
 
or a pharmaceutically acceptable salt thereof.
       

     A method for treating diabetes and related diseases employing the above compounds is also provided.

This application is a continuation of U.S. application Ser. No.11/769,964 filed on Jun. 28, 2007, now allowed, which claims priority toU.S. Provisional Application No. 60/818,912 filed Jul. 6, 2006, whosecontents are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel phosphonate and phosphinatecompounds which are activators of the enzyme glucokinase and thus areuseful in treating diabetes, and to a method for treating diabetes,especially Type II diabetes, using such compounds.

BACKGROUND OF THE INVENTION

The enzyme glucokinase (GK), which is mainly found in pancreatic β-cellsand liver parenchymal cells, catalyzes the conversion of glucose toglucose-6-phosphate, which is the first step in the metabolism ofglucose. Glucokinase is also a rate-controlling enzyme for glucosemetabolism in pancreatic β-cells and liver parenchymal cells, which playan important role in whole-body glucose homeostasis.

Liag, Y. et al., (Biochem. J., 1995, 309:167-173) report the findingthat Type II (maturity-onset) diabetes of the young (MODY-2) is causedby loss of function mutations in the glucokinase gene, which suggeststhat glucokinase also functions as a glucose sensor in humans. Thus,compounds that activate glucokinase and thus increase the sensitivity ofthe glucokinase sensor system and thereby cause increase in insulinsecretion will be useful in the treatment of hyperglycemia and Type IIdiabetes.

Glucokinase activators have been demonstrated to be effective inenhancing: 1) the effect of glucose on insulin release from isolated ratand human pancreatic islets, and 2) the glucose induction of pancreaticislet glucokinase in isolated cultured rat islets (e.g. Matschinsky, F.M. et al., Diabetes, 2006, 55:1, and (“Glucokinase and Glycemic Disease,from Basics to Novel Therapeutics”, published by Karger, 2004; F. M.Matschinsky and M. A. Magnuson, eds., Ch. 6, pp. 360-378). In diabeticanimal model studies, glucokinase activators have been demonstrated tostimulate insulin release, enhance glycogen synthesis and reduce hepaticglucose production in pancreatic clamp studies. Importantly, glucokinaseactivators have been demonstrated to dose-dependently lower bloodglucose levels in different standard animal models of type 2 diabetes,such as the ob/ob mouse, db/db mouse and Zucker in acute single-dosestudies and also effectively improved the glucose excursion in bothnormal C57/BL6J and ob/ob mice in oral glucose tolerance tests (e.g. in“Glucokinase and Glycemic Disease, from Basics to Novel Therapeutics”,published by Karger, 2004; F. M. Matschinsky and M. A. Magnuson, eds.,Ch. 6, pp. 360-378 as well as Fyfe, M. C. et al., Diabetologia, 2007,50:1277).

Glucokinase activators have also demonstrated antidiabetic efficacy inchronic animal models of type II diabetes. For instance, in a 9-daystudy in ob/ob mice, a glucokinase activator improved the overallglucose profile while showing comparable antihyperglycemic effects inoral glucose tolerance tests at the beginning and end of the study(Fyfe, M. C. et al., Diabetologia, 2007, 50:1277). In another instance,in a chronic 40-week study, a glucokinase activator prevented thedevelopment of hyperglycemia in diet-induced obese mice which wereglucose intolerant. The diet-induced obese mice treated with aglucokinase activator showed marked improvement in the glucose excursionin an oral glucose tolerance test at the end of the study relative tothe control group (“Glucokinase and Glycemic Disease, from Basics toNovel Therapeutics”, published by Karger, 2004; F. M. Matschinsky and M.A. Magnuson, eds., Ch. 6, pp. 360-378).

SUMMARY OF THE INVENTION

In accordance with one aspect of the invention, compounds are providedhaving the structure I

wherein

R₁ is a heteroaryl substituted by R₄ and optionally substituted with oneor two substituents R₅ and/or R₆, wherein the heteroaryl possesses anitrogen atom adjacent to the atom joining said heteroaryl group to

R₄ is —(CH₂)_(n)—Z—(CH₂)_(m)—PO(OR₇)(OR₈),

-   -   or —(CH₂)_(n)Z—(CH₂)_(n), —PO(OR₂)R₉,    -   or —(CH₂)_(n)—Z—(CH₂)_(m)—O—PO(OR₂)R₉,    -   or —(CH₂)_(n)Z—(CH₂)_(m)—O—PO—(R₉)R₁₀,    -   or —(CH₂)_(n)Z—(CH₂)_(m)—PO(R₉)R₁₀;

R₇ and R₈ are the same or different and are independently selected fromhydrogen and alkyl;

R₉ and R₁₀ are the same or different and are independently selected fromalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, any of which maybe optionally substituted;

additionally, R₇ and R₈ can be cyclized into a ring

similarly, R₇ and R₉ can be cyclized into a ring

similarly, R₉ and R₁₀ can be cyclized into a ring

Z is selected from a bond, alkylene and alkenylene, each of which may beoptionally substituted (e.g. hydroxy, alkoxy, aminoalkyl, aminoaralkyl,aminoheteroaralkyl, aminoaryl, aminoheteroaryl or carboxy);

m is 0, 1 or 2;

n is 0, 1 or 2;

and Z may be O, S, SO₂ when

m is 1 or 2,

n is 0, 1, or 2;

R₅ and R₆ are the same or different and are independently selected fromhydrogen, alkyl, halogen or carboxyl, or is absent;

X is selected from

and when Y is absent, X is selected from

R₂ is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkynyl, and alkenyl (all of which may be optionallysubstituted);

p is 0 or 1;

Q is selected from O, S(O)_(q) and CO, where q is 0, 1 or 2;

Q₁ is selected from hydrogen and fluorine;

R₁₁ is selected from hydrogen, lower alkyl, cycloalkyl, aryl andheteroaryl;

R₁₂ is selected from hydrogen, and lower alkyl, or R₁₁ and R₁₂ togetherwith the carbon atom to which they are attached form a cycloalkyl ringof 5 to 7 carbon atoms;

R₁₃ is selected from halo, nitro, amino, cyano, methyl, trifluoromethyl,hydroxy, methoxy, trifluoromethoxy, methylthio, methylsulfinyl andmethylsulfonyl;

T is selected from aryl and heteroaryl, each of which may be optionallysubstituted;

Y is R₃—(CH₂)_(s)—, or is absent;

where R₃ is aryl or heteroaryl, each of which may be optionallysubstituted;

s is 0 or 1;

all stereoisomers thereof, a prodrug ester thereof or a pharmaceuticallyacceptable salt thereof.

Preferably in compounds of formula I

X is

where more preferably n is 1, and R₂ is a cycloalkyl, preferablycyclopentyl or cyclohexyl, or R₂ is a heterocyclyl group such ascycloalkyl with an embedded hetero atom such as an oxygen atom or asulfur atom, for example tetrahydropyran, tetrahydrofuran,

preferably tetrahydropyran;

Y is aryl or heteroaryl or is absent, still more preferably aryl, morepreferably phenyl, still more preferably

or X is a bond and Y is

R₄ is (CH₂)_(n)—Z—(CH₂)_(m)—PO(OR₇)(OR₈) wherein Z is alkylene oralkenylene,

wherein n is 0, m is 0 and Z is a bond, —CH₂—, —CH₃—CH═CH—, —CH₂CH₂— or

and

R₅ and R₆ are each H;

R₇ is H or alkyl; and

R₈ is H or alkyl.

The moiety

is preferably

R₄ is more preferably

Preferred embodiments of Y—X—CO— wherein X is X-1 include, but are notlimited to:

Preferred embodiments of Y—X—CO— wherein X═X-2 include, but are notlimited to:

Preferred embodiments of Y—X—CO— wherein X═X-3 include, but are notlimited to:

Preferred embodiments of Y—X—CO— wherein X═X-4 include, but are notlimited to:

Preferred embodiments of Y—X—CO— wherein X═X-5 include, but are notlimited to:

Preferred embodiments of Y—X—CO— wherein X═X-6 (wherein X is a bond)include, but are not limited to:

Preferred embodiments of Y—X—CO— wherein X═X-7 include, but are notlimited to:

Preferred embodiments of Y—X—CO— wherein X═X-8 include, but are notlimited to:

Preferred embodiments of Y—X—CO— wherein X═X-9 include, but are notlimited to:

Examples of preferred compounds in accordance with the present inventioninclude, but are not limited to, the following:

The compounds of the present invention activate or enhance the activityof the enzyme glucokinase. Consequently, the compounds of the presentinvention may be used in the treatment of multiple diseases or disordersassociated with a deficit of glucokinase, such as diabetes and relatedconditions, microvascular complications associated with diabetes, themacrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, and othermaladies. Examples of diseases or disorders associated with deficit inactivity of the enzyme glucokinase that can be prevented, inhibited, ortreated according to the present invention include, but are not limitedto, diabetes, hyperglycemia, impaired glucose tolerance, insulinresistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy,delayed wound healing, atherosclerosis and its sequelae, abnormal heartfunction, myocardial ischemia, stroke, Metabolic Syndrome, hypertension,obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia,infection, cancer, vascular restenosis, pancreatitis, neurodegenerativedisease, lipid disorders, cognitive impairment and dementia, bonedisease, HIV protease associated lipodystrophy, and glaucoma.

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds, and for methods ofusing such compounds. In particular, the present invention provides apharmaceutical composition containing a therapeutically effective amountof a compound of formula I, alone or in combination with apharmaceutically acceptable carrier.

Further, in accordance with the present invention, a method is providedfor preventing, inhibiting, or treating the progression or onset ofdiseases or disorders associated with deficit in the activity of theenzyme glucokinase, such as defined above and hereinafter, wherein atherapeutically effective amount of a compound of formula I isadministered to a mammalian, i.e., human, patient in need of treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other therapeutic agent(s).

Further, the present invention provides a method for preventing,inhibiting, or treating the diseases as defined above and hereinafter,wherein a therapeutically effective amount of a combination of acompound of formula I and another compound of formula I and/or at leastone other type of therapeutic agent, is administered to a mammalian,i.e., human, patient in need of treatment.

In another embodiment, compounds of the present invention are selectedfrom the compounds exemplified in the examples.

In another embodiment, the present invention relates to pharmaceuticalcompositions which include of a therapeutically effective amount of acompound of the present invention, alone or, optionally, in combinationwith a pharmaceutically acceptable carrier and/or one or more otheragent(s).

In another embodiment, the present invention relates to methods ofenhancing the activity of the enzyme glucokinase which includes the stepof administering to a mammalian patient, for example, a human patient,in need thereof a therapeutically effective amount of a compound of thepresent invention, alone, or optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of diseasesor disorders associated with deficit in the activity of the enzymeglucokinase which includes the step of administering to a mammalianpatient, for example, a human patient, in need of prevention,inhibition, or treatment a therapeutically effective amount of acompound of the present invention, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

Examples of diseases or disorders associated with the deficit inactivity of the enzyme glucokinase that can be prevented, inhibited, ortreated according to the present invention include, but are not limitedto, are those diseases or disorders set out above.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdiabetes, hyperglycemia, obesity, dyslipidemia, hypertension, andcognitive impairment which includes the step of administering to amammalian patient, for example, a human patient, in need of prevention,inhibition, or treatment a therapeutically effective amount of acompound of the present invention, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

In still another embodiment, the present invention relates to a methodfor preventing, inhibiting, or treating the progression or onset ofdiabetes, which includes the step of administering to a mammalianpatient, for example, a human patient, in need of prevention,inhibition, or treatment a therapeutically effective amount of acompound of the present invention, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

In yet still another embodiment, the present invention relates to amethod for preventing, inhibiting, or treating the progression or onsetof hyperglycemia which includes the step of administering to a mammalianpatient, for example, a human patient, in need of prevention,inhibition, or treatment a therapeutically effective amount of acompound of the present invention, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of obesitywhich includes the step of administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In one embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdyslipidemia, which includes the step of administering to a mammalianpatient, for example, a human patient, in need of prevention,inhibition, or treatment a therapeutically effective amount of acompound of the present invention, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms, and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalency is not exceeded, and that the substitution results in a stablecompound. When a substituent is keto (i.e., ═O), then 2 hydrogens on theatom are replaced.

When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

Unless otherwise indicated, the term “lower alkyl,” “alkyl,” or “alk” asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 20 carbons, preferably1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groups mayoptionally include 1 to 4 substituents such as halo, for example F, Br,Cl, or I, or CF₃, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl, and/oralkylthio as well as (═O), OR_(a), SR_(a), (═S), —NR_(a)R_(b),

—N(alkyl)₃ ⁺, —NR_(a)SO₂, —NR_(a)SO₂R_(c), —SO₂R_(c)—SO₂NR_(a)R_(b),—SO₂NR_(a)C(═O)R_(b), SO₃H, —PO(OH)₂, —C(═O)R_(a), —CO₂R_(a),—C(═O)NR_(a)R_(b), —C(═O)(C₁₋₄alkylene)NR_(a)R_(b),—C(═O)NR_(a)(SO₂)R_(b), —CO₂(C₁₋₄alkylene)NR_(a)R_(b),—NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b), —NR_(a)(C₁₋₄alkylene)CO₂R_(b),═N—OH, ═N—O-alkyl, wherein R_(a) and R_(b) are the same or different andare independently selected from hydrogen, alkyl, alkenyl, CO₂H,CO₂(alkyl), C₃₋₇cycloalkyl, phenyl, benzyl, phenylethyl, naphthyl, afour to seven membered heterocyclo, or a five to six memberedheteroaryl, or when attached to the same nitrogen atom may join to forma heterocyclo or heteroaryl, and R_(c) is selected from same groups asR_(a) and R_(b) but is not hydrogen. Each group R_(a) and R_(b) whenother than hydrogen, and each R_(c) group optionally has up to threefurther substituents attached at any available carbon or nitrogen atomof R_(a), R_(b), and/or R_(c), said substituent(s) being the same ordifferent and are independently selected from the group consisting of(C₁₋₆)alkyl, (C₂₋₆)alkenyl, hydroxy, halogen, cyano, nitro, CF₃,O(C₁₋₆alkyl), OCF₃, C(═O)H, C(═O)(C₁₋₆alkyl), CO₂H, CO₂(C₁₋₆alkyl),NHCO₂(C₁₋₆alkyl), —S(C₁₋₆alkyl), —NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)₂,N(CH₃)₃ ⁺, SO₂(C₁₋₆alkyl), C(═O)(C₁₋₄alkylene)NH₂,C(═O)(C₁₋₄alkylene)NH(alkyl), C(═O)(C₁₋₄alkylene)N(C₁₋₄alkyl)₂,C₃₋₇cycloalkyl, phenyl, benzyl, phenylethyl, phenyloxy, benzyloxy,naphthyl, a four to seven membered heterocylo, or a five to six memberedheteroaryl. When a substituted alkyl is substituted with an aryl,heterocyclo, cycloalkyl, or heteroaryl group, said ringed systems are asdefined below and thus may have zero, one, two, or three substituents,also as defined below.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (orbicycloalkyl), and tricyclic alkyl, containing a total of 3 to 20carbons forming the ring, preferably 3 to 10 carbons, forming the ringand which may be fused to 1 or 2 aromatic rings as described for aryl,which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/orany of the substituents for alkyl.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons,and more preferably 1 to 8 carbons in the normal chain, which includeone to six double bonds in the normal chain, such as vinyl, 2-propenyl,3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl,2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, andwhich may be optionally substituted with 1 to 4 substituents, namely,halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino,alkylamido, arylcarbonyl-amino, nitro, cyano, thiol, alkylthio, and/orany of the alkyl substituents set out herein.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbonsand more preferably 2 to 8 carbons in the normal chain, which includeone triple bond in the normal chain, such as 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl,4-dodecynyl, and the like, and which may be optionally substituted with1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, and/or any of the alkylsubstituents set out herein.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine as well as CF₃,with chlorine or fluorine being preferred.

Unless otherwise indicated, the term “aryl” as employed herein alone oras part of another group refers to monocyclic and bicyclic aromaticgroups containing 6 to 10 carbons in the ring portion (such as phenyl,biphenyl or naphthyl, including 1-naphthyl and 2-naphthyl) and mayoptionally include 1 to 3 additional rings fused to a carbocyclic ringor a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl, orcycloheteroalkyl rings) for example

The aryl group may be optionally substituted through available carbonatoms with 1, 2, or 3 substituents, for example, hydrogen, halo,haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl,cycloalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl,arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo,heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy,hydroxy, nitro, cyano, amino, substituted amino wherein the aminoincludes 1 or 2 substituents (which are alkyl, aryl, or any of the otheraryl compounds mentioned in the definitions), thiol, alkylthio,arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkyl-aminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino,or arylsulfon-aminocarbonyl, OR_(a), SR_(a), (═S), —NR_(a)R_(b),—N(alkyl)₃ ⁺, —NR_(a)SO₂, —NR_(a)SO₂R_(c), —SO₂R_(c)—SO₂NR_(a)R_(b),—SO₂NR_(a)C(═O)R_(b), SO₃H, —PO(OH)₂, —C(═O)R_(a), —CO₂R_(a),—C(═O)NR_(a)R_(b), —C(═O)(C₁₋₄alkylene)NR_(a)R_(b),—C(═O)NR_(a)(SO₂)R_(b), —CO₂(C₁₋₄alkylene)NR_(a)R_(b),—NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b), or —NR_(a)(C₁₋₄alkylene)CO₂R_(b),wherein R_(a), R_(b) and R_(c) are as defined above for substitutedalkyl groups, and are also in turn optionally substituted as recitedabove. Additionally, two substituents attached to an aryl, particularlya phenyl group, may join to form a further ring such as a fused orspiro-ring, e.g., cyclopentyl or cyclohexyl, or fused heterocyclo orheteroaryl. When an aryl is substituted with a further ring (or has asecond ring fused thereto), said ring in turn is optionally substitutedwith one to two of (C₁₋₄alkyl, (C₂₋₄alkenyl, halogen, hydroxy, cyano,nitro, CF₃, O(C₁₋₄alkyl), OCF₃, C(═O)H, C(═O)(C₁₋₄alkyl), CO₂H,CO₂(C₁₋₄alkyl), NHCO₂(C₁₋₄alkyl), —S(C₁₋₄alkyl), —NH₂, NH(C₁₋₄alkyl),N(C₁₋₄alkyl)₂, N(C₁₋₄alkyl)₃ ⁺, SO₂(C₁₋₄alkyl), C(═O)(C₁₋₄alkylene)NH₂,C(═O)(C₁₋₄alkylene)NH(alkyl), and/or C(═O)(C₁₋₄alkylene)N(C₁₋₄alkyl)₂and/or any of the alkyl substituents set out herein.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy”or “aralkoxy” as employed herein alone or as part of another groupincludes any of the above alkyl, aralkyl, or aryl groups linked to anoxygen atom.

Unless otherwise indicated, the term “amino” as employed herein alone oras part of another group refers to amino that may be substituted withone or two substituents, which may be the same or different, such asalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, or thioalkyl. These substituents may befurther substituted with a carboxylic acid and/or any of the R₃ groupsor substituents for R₃ as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl, or hydroxy.

Unless otherwise indicated, the term “lower alkylthio,” “alkylthio,”“arylthio,” or “aralkylthio” as employed herein alone or as part ofanother group includes any of the above alkyl, aralkyl, or aryl groupslinked to a sulfur atom.

Unless otherwise indicated, the term “lower alkylamino,” “alkylamino,”“arylamino,” or “arylalkylamino” as employed herein alone or as part ofanother group includes any of the above alkyl, aryl, or arylalkyl groupslinked to a nitrogen atom.

The term “acyl” alone or as part of another group refers to a carbonylgroup linked to an organic radical, more particularly, the groupC(═O)R_(e), as well as the bivalent groups —C(═O)— or —C(═O)R_(e)—,which are linked to organic radicals. The group R_(e) can be selectedfrom alkyl, alkenyl, alkynyl, aminoalkyl, substituted alkyl, substitutedalkenyl, or substituted alkynyl, as defined herein, or when appropriate,the corresponding bivalent group, e.g., alkylene, alkenylene, and thelike.

The term “heterocyclo” or “heterocyclic” or “heterocyclyl” or“cycloheteroalkyl” refers to substituted and unsubstituted non-aromatic3 to 7 membered monocyclic groups, 7 to 11 membered bicyclic groups, and10 to 15 membered tricyclic groups, in which at least one of the ringshas at least one heteroatom (O, S, or N) (also referred to ascycloheteroalkyl or heterocycloalkyl). Each ring of the heterocyclogroup containing a heteroatom can contain one or two oxygen or sulfuratoms and/or from one to four nitrogen atoms provided that the totalnumber of heteroatoms in each ring is four or less, and further providedthat the ring contains at least one carbon atom. The fused ringscompleting bicyclic and tricyclic groups may contain only carbon atomsand may be saturated, partially saturated, or unsaturated. The nitrogenand sulfur atoms may optionally be oxidized and the nitrogen atoms mayoptionally be quaternized. The heterocyclo group may be attached at anyavailable nitrogen or carbon atom. The heterocyclo ring may containzero, one, two, or three substituents selected from the group consistingof halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, nitro, cyano, oxo (═O), OR_(a),SR_(a), (═S), —NR_(a)R_(b), —N(alkyl)₃ ⁺, NR_(a)SO₂, —NR_(a)SO₂R_(c),—SO₂R_(c)—SO₂NR_(a)R_(b), —SO₂NR_(a)C(═O)R_(b), SO₃H, —PO(OH)₂,—C(═O)R_(a), —CO₂R_(a), —C(═O)NR_(a)R_(b),—C(═O)(C₁₋₄alkylene)NR_(a)R_(b), —C(═O)NR_(a)(SO₂)R_(b),—CO₂(C₁₋₄alkylene)NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b),—NR_(a)(C₁₋₄alkylene)CO₂R_(b), ═N—OH, ═N—O-alkyl, aryl, cycloalkyl,heterocyclo, and/or heteroaryl, wherein R_(a), R_(b), and R_(c) are asdefined above for substituted alkyl groups, and are also in turnoptionally substituted as recited above. When a heterocyclo issubstituted with a further ring, said ring in turn is optionallysubstituted with one to two of (C₁₋₄)alkyl, (C₂₋₄alkenyl, halogen,hydroxy, cyano, nitro, CF₃, O(C₁₋₄alkyl), OCF₃, C(═O)H,C(═O)(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄alkyl), NHCO₂(C₁₋₄alkyl), —S(C₁₋₄alkyl),—NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, N(C₁₋₄alkyl)₃ ⁺, SO₂(C₁₋₄alkyl),C(═O)(C₁₋₄alkylene)NH₂, C(═O)(C₁₋₄alkylene)NH(alkyl), and/orC(═O)(C₁₋₄alkylene)N(C₁₋₄alkyl)₂.

Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl,imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl.

Preferred heterocyclo groups in compounds of formula (I) include

which optionally may be substituted.

The term “heteroaryl” alone or as part of another group refers tosubstituted and unsubstituted aromatic 5 or 6 membered monocyclicgroups, 9 or 10 membered bicyclic groups, and 11 to 14 memberedtricyclic groups which have at least one heteroatom (O, S or N) in atleast one of the rings. Each ring of the heteroaryl group containing aheteroatom can contain one or two oxygen or sulfur atoms and/or from oneto four nitrogen atoms provided that the total number of heteroatoms ineach ring is four or less and each ring has at least one carbon atom.The fused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated, and may include aryl, cycloalkyl, heteroaryl orcycloheteroaryl. The nitrogen and sulfur atoms may optionally beoxidized and the nitrogen atoms may optionally be quaternized.Heteroaryl groups which are bicyclic or tricyclic must include at leastone fully aromatic ring but the other fused ring or rings may bearomatic or non-aromatic. The heteroaryl group may be attached at anyavailable nitrogen or carbon atom of any ring. The heteroaryl ringsystem may contain zero, one, two or three substituents which may be anyof the substituents set out for alkyl and can be selected from the groupconsisting of halogen, trifluoromethyl, trifluoromethoxy, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, nitro, cyano,OR_(a), SR_(a), (═S), —NR_(a)R_(b), —N(alkyl)₃ ⁺, —NR_(a)SO₂,—NR_(a)SO₂R_(c), —SO₂R_(c)—SO₂NR_(a)R_(b), —SO₂NR_(a)C(═O)R_(b), SO₃H,—PO(OH)₂, —C(═O)R_(a), —CO₂R_(a), —C(═O)NR_(a)R_(b),—C(═O)(C₁₋₄alkylene)NR_(a)R_(b), —C(═O)NR_(a)(SO₂)R_(b),—CO₂(C₁₋₄alkylene)NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b),—NR_(a)(C₁₋₄alkylene)CO₂R_(b), aryl, cycloalkyl, heterocyclo, and/orheteroaryl, wherein R_(a), R_(b) and R_(c) are as defined above forsubstituted alkyl groups, and are also in turn optionally substituted asrecited above. When a heteroaryl is substituted with a further ring,said ring in turn is optionally substituted with one to two of(C₁₋₄alkyl, (C₂₋₄alkenyl, halogen, hydroxy, cyano, nitro, CF₃,O(C₁₋₄alkyl), OCF₃, C(═O)H, C(═O)(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄alkyl),NHCO₂(C₁₋₄alkyl), —S(C₁₋₄alkyl), —NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,N(C₁₋₄alkyl)₃ ⁺, SO₂(C₁₋₄alkyl), C(═O)(C₁₋₄alkylene)NH₂,C(═O)(C₁₋₄alkylene)NH(alkyl), and/or C(═O)(C₁₋₄alkylene)N(C₁₋₄alkyl)₂.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

In compounds of formula (I), preferred heteroaryl groups include

and the like.

The term “heterocyclylalkyl” or “heterocycloalkyl” or“cycloheteroalkylakyl” as used herein alone or as part of another grouprefers to heterocyclyl groups as defined above linked through a C atomor heteroatom to an alkyl chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to an alkyl chain, alkylene,or alkenylene as defined above.

The term “cyano” as used herein, refers to a —CN group.

The term “nitro” as used herein, refers to an —NO₂ group.

The term “hydroxy” as used herein, refers to an —OH group.

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl),heterocyclo (e.g., pyrrolidinyl) or heteroaryl (e.g., imidazolyl),unless otherwise specifically indicated the reference is intended toinclude rings having 0 to 3, preferably O-2, substituents selected fromthose recited above for the aryl, cycloalkyl, heterocyclo and/orheteroaryl groups, as appropriate.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

The term “carbocyclic” means a saturated or unsaturated monocyclic orbicyclic ring in which all atoms of all rings are carbon. Thus, the termincludes cycloalkyl and aryl rings. The carbocyclic ring may besubstituted in which case the substituents are selected from thoserecited above for cycloalkyl and aryl groups.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof.

The terms pharmaceutically acceptable “salt” and “salts” may refer tobasic salts formed with inorganic and organic bases. Such salts includeammonium salts; alkali metal salts, such as lithium, sodium, andpotassium salts (which are preferred); alkaline earth metal salts, suchas calcium and magnesium salts; salts with organic bases, such as aminelike salts (e.g., dicyclohexylamine salt, benzathine,N-methyl-D-glucamine, and hydrabamine salts); and salts with amino acidslike arginine, lysine, and the like; and zwitterions, the so-called“inner salts.” Nontoxic, pharmaceutically acceptable salts arepreferred, although other salts are also useful, e.g., in isolating orpurifying the product.

The term pharmaceutically acceptable “salt” and “salts” also includesacid addition salts. These are formed, for example, with stronginorganic acids, such as mineral acids, for example sulfuric acid,phosphoric acid, or a hydrohalic acid such as HCl or HBr, with strongorganic carboxylic acids, such as alkanecarboxylic acids of 1 to 4carbon atoms which are unsubstituted or substituted, for example, byhalogen, for example acetic acid, such as saturated or unsaturateddicarboxylic acids, for example oxalic, malonic, succinic, maleic,fumaric, phthalic, or terephthalic acid, such as hydroxycarboxylicacids, for example ascorbic, glycolic, lactic, malic, tartaric, orcitric acid, such as amino acids, (for example aspartic or glutamic acidor lysine or arginine), or benzoic acid, or with organic sulfonic acids,such as (C₁-C₄) alkyl or arylsulfonic acids, which are unsubstituted orsubstituted, for example by halogen, for example methanesulfonic acid orp-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

The term “prodrug” denotes a compound which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of the formula, and/or a salt and/orsolvate thereof. For example, compounds containing a carboxy group canform physiologically hydrolyzable esters which serve as prodrugs bybeing hydrolyzed in the body to yield formula compounds per se. Suchprodrugs are preferably administered orally since hydrolysis in manyinstances occurs principally under the influence of the digestiveenzymes. Parenteral administration may be used where the ester per se isactive, or in those instances where hydrolysis occurs in the blood.

The term “prodrugs” as employed herein includes esters and carbonatesformed by reacting one or more hydroxyls of compounds of formula I withalkyl, alkoxy, or aryl substituted acylating agents employing proceduresknown to those skilled in the art to generate acetates, pivalates,methylcarbonates, benzoates, and the like.

Various forms of prodrugs are well known in the art and are describedin:

-   a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al.,    Ch. 31 (Academic Press, 1996);-   b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson    and H. Bundgaard, eds. Ch. 5, pp. 113-191 (Harwood Academic    Publishers, 1991); and-   d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and    Joachim M. Mayer, (Wiley-VCH, 2003).    Said references are incorporated herein by reference.

Examples of physiologically hydrolyzable esters of compounds of formula(I) include C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl,pivaloyloxymethyl, or propionyloxymethyl,C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g. methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl, and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Prodrug ester examples include the following groups:(1-alkanoyloxy)alkyl such as,

wherein R^(z), R^(t), and R^(y) are H, alkyl, aryl, or arylalkyl;however, R^(z)O cannot be HO.

Examples of such prodrug esters include

Other examples of suitable prodrug esters include

wherein R^(z) can be H, alkyl (such as methyl or t-butyl), arylalkyl(such as benzyl) or aryl (such as phenyl); R^(v) is H, alkyl, halogen oralkoxy, R^(u) is alkyl, aryl, arylalkyl, or alkoxyl, and n₁ is 0, 1, or2.

The term “tautomer” refers to compounds of the formula I and saltsthereof that may exist in their tautomeric form, in which hydrogen atomsare transposed to other parts of the molecules and the chemical bondsbetween the atoms of the molecules are consequently rearranged. Itshould be understood that the all tautomeric forms, insofar as they mayexist, are included within the invention.

In addition, compounds of the formula I are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% formula Icompound (“substantially pure” compound I), which is then used orformulated as described herein. Such “substantially pure” compounds ofthe formula I are also contemplated herein as part of the presentinvention.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents and/orexhibit polymorphism. Consequently, compounds of formula I can exist inenantiomeric, or diastereomeric forms, or in mixtures thereof. Theprocesses for preparation can utilize racemates, enantiomers, ordiastereomers as starting materials. When diastereomeric or enantiomericproducts are prepared, they can be separated by conventional methods forexample, chromatographic or fractional crystallization.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to treat orprevent diabetes and/or obesity.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Synthesis

Compounds of formulae I and Ia may be prepared as shown in the followingreaction schemes and the description thereof, as well as relevantliterature procedures that may be used by one skilled in the art.Exemplary reagents and procedures for these reactions appear hereinafterand in the working Examples. Protection and deprotection in the Schemesbelow may be carried out by procedures generally known in the art (see,for example, Greene, T. W. and Wuts, P.G.M., Protecting Groups inOrganic Synthesis, 3^(rd) Edition, 1999 [Wiley]).

The synthesis of amide compounds of formula I wherein X=

and when Y is absent,

is described in Scheme 1. The carboxylic acid 1 is coupled with amine 2followed standard literature conditions, such as: (1) the use of oxalylchloride with catalytic DMF to form the acid chloride intermediatefollowed by subsequent reaction with amine 2 in the presence of an aminebase; or (2) the treatment of a mixture of 1 and 2 with a couplingreagent such as DEPBT (Li et al., Org. Lett., 1999, 1:91). Where theheteroaromatic ring R₁ is depicted in Scheme 1 and in all subsequentschemes described below, the optional ring substituents R₅ and R₆ may bepresent.

Procedures for the synthesis of pertinent examples of carboxylic acid 1can be found in the literature (references include, but are not limitedto, the following PCT Intl. Applications: for X-1, WO 2000/058293, WO2001/083465, WO 2001/085706, WO 2001/085707, WO 2002/046173, WO2003/095438, WO 2004/052869, WO 2004/072031, WO 2004/063194, WO2004/072066, WO 2005/103021, WO 2006/016194, WO 2006/016174, WO2006/016178; for X-2, WO 2002/008209, WO 2004/063194; for X-4, WO2001/044216, WO 2004/072031, WO 2004/072066, WO 2004/063194, WO2002/014312, WO 2005/103021, WO 2006/016194; for X-5, WO 2004/063179;for X-6, WO 2003/000262, WO 2003/000267, WO 2003/080585, WO 2003/015774,WO 2004/045614, WO 2004/046139, WO 2004/076420, WO 2005/121110; WO2006/040528, WO 2006/040529, WO 2006/125972, WO 2007/007040, WO2007/007041, WO 2007/007042, WO 2007/0017649; for X-7, WO 2001/083478;for X-8, WO 2002/048106; for X-9, WO 2004/031179.

The synthesis of urea compounds of formula I wherein

is described in Scheme 2. The amine 3 may be treated with a reagent suchas carbonyldiimidazole, 4-nitrophenylchloroformate, phosgene, or aphosgene derivative such as diphosgene or triphosgene, followed by theaddition of amine 2 to afford the desired urea product of formula I.Alternatively, amine 2 may be first treated with a reagent such ascarbonyldiimidazole (or other like reagents as described above),followed by addition of amine 3 to provide ureas of formula I-A.

Procedures for the synthesis of pertinent examples of amine 3 areavailable in the literature (references include PCT Int. ApplicationsWO2003/055482 and WO2004/002481; and Castellano et al., Bioorg. Med.Chem. Leu. 2005, 15:1501).

Scheme 3 describes a general approach to the synthesis of amine 2Awherein

R₄=—(CH₂)_(n)—Z—(CH₂)_(m)—PO(OR₇)(OR₈)

-   -   Z=bond    -   m and n=0        i.e., where the resulting phosphonate group is directly attached        to the heteroaromatic ring, R₁. A protected amino-substituted        heteroaryl 4 with a suitably activated hydrogen substituent is        deprotonated with a strong base such as LDA or n-butyllithium.        The resulting anion is reacted with a dialkylchlorophosphate 5        resulting in direct attachment of the phosphonate group to R₁.        Removal of the protecting groups provides amine 2A.        Alternatively, the halo-substituted heteroaryl 6 can also be        converted to the same anionic intermediate via halogen-metal        exchange by reaction with a base such as n-butyllithium. This        approach can also be extended to the synthesis of phosphinic        acids by the use of a reagent such as        N,N-diethylchloromethylphosphonamide to react with the anion        intermediate (Rumthao et al., Bioorg. Med. Chem. Leu., 2004,        14:5165-5170). As an example, the protected thiazole amine 7 may        be deprotonated as shown in Scheme 3 using a base such as LDA or        n-BuLi and phosphonylated as described to give, after        deprotection, the 5-phosphonate-substituted thiazole amine 2B        (South et al., J. Het. Chem., 1991, 28:1017).

The reactions described in Scheme 3 above and Schemes 4, 5, 6, 7 and 8below may also be conducted on compounds wherein the group Y—X—CO— hasalready been acylated to the amine 2 and where the chemistry is allowedby compatible structure in Y—X—CO— and/or the use of appropriateprotecting groups.

Scheme 4 describes another approach to the synthesis of amine 2A. Theprotected heteroaryl amine 8 containing a substituent such as bromo,iodo or triflate is coupled to dialkylphosphite 9 in the presence of acatalytic amount of palladium(0) catalyst, such astetrakis-triphenylphosphine palladium(0) to provide, after deprotection,the phosphonate substituted heteroaryl amine 2A (Hirao et al.,Synthesis, 1981, 56-57). The use of the reagent 10 in this reactionprovides the corresponding phosphinate 2C (Rumthao et al., Bioorg. Med.Chem. Lett., 2004, 14:5165-5170). As an example, the reaction betweenthe bromo pyridine 11 and dialkylphosphite 9 catalyzed by Pd(Ph₃P)₄provides the phosphonylated pyridine compound I-B. Compound II isobtained by coupling acid 1 to 5-bromo-2-aminopyrazine in the mannerdescribed in Scheme 1.

Scheme 5 describes the synthesis of compounds of formula I in which

R₄=—(CH₂)_(n)—Z—(CH₂)_(m)—PO(OR₇)(OR₈)

-   -   Z=alkene or ethylene    -   m and n=0        thus connecting the phosphonate group to the heteroaromatic ring        with a two-carbon linker. A suitably protected heteroaryl amine        8 is coupled to vinyl phosphonate 12 in the presence of        catalytic amounts of a Pd(II) catalyst such as Pd(OAc)₂ and        phosphine ligand such as tri-o-tolylphosphine to give a        protected vinyl phosphonate intermediate product (Xu et al.,        Synthesis, 1983, 556-558). Removal of protecting groups yields        the vinyl phosphonate amine 2D which is converted to I-D, the        corresponding compound of formula I wherein Z=alkene (vinyl) by        the manner described in Schemes 1 and 2. Hydrogenation in the        presence of catalytic Pd(0) of 2D and 1D provides the        corresponding ethylene (two-carbon) linked phosphonate        compounds, 2E and 1-E. As mentioned earlier, these        transformations can be conducted on a fully elaborated        intermediate such as described conversion of aminopyrazine amide        11 to the vinyl phosphonate substituted pyrazine product I-F.

Scheme 6 describes the synthesis of compounds of formula I in which thephosphonate or phosphinate groups in R₄ are incorporated using theArbusov (Engel, R., Handbook of Organophosphorus Chemistry, 1992 [MarcelDekker]) or Michaelis-Becker (Engel, R., Handbook of OrganophosphorusChemistry, 1992 [Marcel Dekker]) reactions. In the Arbusov reaction, thealkyl halide 13 is heated with the trialkylphosphite 14 to yield, afterremoval of protecting groups, amine 2F Amine 2F is converted tocompounds of formula IG by means described in Schemes 1 and 2. Whencarried out using R₉P(OR₇)₂ instead of the trialkylphosphite 14, thecorresponding phosphinic ester product is obtained (i.e., whereR₄=—(CH₂)_(n)—Z—(CH₂)_(m)—PO—(R₉)(OR₇) (Kapustin et al., Org. Leu.,2003, 5:3053-3057). In the Michaelis-Becker reaction, compound 13 isreacted with dialkylphosphite 15 in the presence of base to yield, afterremoval of protecting groups, amine 2F Amine 2F can be converted tocompounds of formula I-G by means described in Schemes 1 and 2. As anexample, the Boc-protected 5-bromomethylpyrazine can heated withtrialkylphosphite 14 to give, after removal of the Boc group, thephosphonomethyl-substituted pyrazine amine 2G, which can be converted tocompounds of formula I as described above.

Scheme 7 describes the synthesis compounds of formula 1 in which the R₁heteroaromatic ring is a thiazole. In this scheme, the phosphonate orphosphinate group in incorporated into an acyclic precursor to theformation of the heteroaromatic ring. In a standard Hantzsch thiazolesynthesis, haloketone 16 is reacts with thiourea 17 to form the4-substituted, 2-aminothiazole 2H. As an example, acetylphosphonic acid18 is treated with bromine to form the α-haloketone 19. The reaction of19 with thiourea 17 affords the 5-phosphono-2-aminothiazole 21 (Ohler etal., Chem. Ber., 1984, 117:3034-3047). The aminothiazoles 2H and 2I maybe converted to compounds of formula I by means described in Scheme 1and 2.

Scheme 8 describes the synthesis of compounds of formula I in which

R₄=—(CH₂)_(n)—Z—(CH₂)_(m)—PO(OR₇)(OR₈)

-   -   Z═CH(OH)    -   m=0, 1    -   n=0, 1, 2        i.e., compounds in which R₄ contains a hydroxy-substituted        methylene [Z═CH(OH)] positioned between the heteroaromatic ring        R₁ and the phosphonate group. In equation (1), reaction of        dialkylphosphite 9 with aldehyde 22 in the presence of a base        such as triethylamine or DBN gives the hydroxyphosphonate        product I-H (Caplan et al., J. Chem. Soc. Perkin 1,2000,        3:421-437), representing a compound of formula I in which        Z═CH(OH), n=0, 1, 2 and m=0. In equation (2), alkyl phosphonate        23 is treated with a base such as n-BuLi, followed by addition        of aldehyde 22 gives the hydroxyphosphonate product I-I        (Mikolajczyk et al., Synthesis, 1984, 691-694), representing a        compound of formula I in which Z═CH(OH), n=0, 1, 2 and m=1. As        examples, the pyrazine 24 and thiazole 25 are converted as shown        to the corresponding hydroxyphosphonates, I-J and I-K.

Scheme 9 describes the synthesis of compounds of formula I in which

R₄=—(CH₂)_(n)—Z—(CH₂)_(m)—PO(OR₇)(OR₈)

-   -   Z═CH(OR₉)    -   m=0    -   n=0, 1, 2        i.e., compounds in which R₄ contains a alkoxy-substituted        methylene [Z═CH(OR₉)] positioned between the heteroaromatic ring        R₁ and the phosphonate group. In equation (1), the        hydroxylphosphonate products of Scheme 8 may be alkylated with        suitable active alkyl halides 26 to give the alpha-alkoxy        phosphonates I-L (Wrobleski et al., Tetrahedron Asymmetry, 2002,        13:845-850). Alternatively, equation (2) depicts the        rhodium-catalyzed insertion reaction of alcohols 28 with        alpha-diazo phosphonates 27 which also provides compounds I-L        (Cox, G. et al., Tetrahedron, 1994, 50:3195-3212; Moody, C. et        al., Tetrahedron Asymmetry, 2001, 12:1657-1661). The preparation        of alpha-diazo phosphonates 28 has been described by direct        diazo transfer to the corresponding ketone 29a (Regitz, M.,        Tetrahedron Lett., 1968, 9:3171-3174). Alternatively, the diazo        phosphonates 28 can be obtained via base-catalyzed decomposition        of the alpha-toluenesulfonylhydrazides derived from the        corresponding keto phosphonates 29b (Marmor, R. et al., J. Org.        Chem., 1971, 36:128-136). The alpha-keto phosphonates 29a may be        synthesized directly from alpha-hydroxy phosphonates (1-H) by        oxidation using a reagent such as CrO₃ (Kaboudin, B. et al.,        Tetrahedron Lett., 2000, 41:3169-2171). Alternatively, the        Arbusov reaction between an acid chloride and trialkylphosphite        yields the corresponding alpha-keto phosphonate (Marmor, R., et        al., J. Org. Chem., 1971, 36:128-136). Methods for the synthesis        of phosphonates such as 29a have been described above.

Scheme 10 describes the synthesis of compounds of formula I in which

R₄=—(CH₂)_(n)—Z—(CH₂)_(m)—PO(OR₇)(OR₈)

-   -   Z═CH(NHR₉)    -   m=0    -   n=0, 1, 2        i.e., compounds in which R₄ contains an amino-substituted        methylene [Z═CH(NHR₉)] positioned between the heteroaromatic        ring R₁ and the phosphonate group. In Scheme 10, aldehyde 22 can        be reacted with a dialkylphosphite 9 and amine 30 to give the        alpha-amino substituted phosphonate I-M by conducting the        reaction in the presence of silica gel and microwave irradiation        (Zhan et al., Chem. Lett., 2005, 34:1042-1043). Other methods        involve preformation of the corresponding imine resulting from        condensation of the aldehyde 22 and amine 30, which is followed        by reaction with the dialkylphosphite 9 in the presence of        various catalysts such as Lewis acids (Laschat and Kunz,        Synthesis, 1992, 90). Furthermore, other catalysts may be used        for the one-pot synthesis described in Scheme 10 (for example,        use of SmI₂ is described in Xu et al., Eur. J. Org. Chem., 2003,        4728).

Scheme 11 describes the synthesis of compounds of formula I in which

R₄=—(CH₂)_(n)—Z—(CH₂)_(m)—O—PO(OR₇)R₉

and —(CH₂)_(n)Z—(CH₂)_(m)—O—PO—R₉R₁₀.

Reaction of the alcohol precursor 31 with the a phosphonyl chloride 32or phosphinyl chloride 33 in the presence of a base such as pyridine ortriethylamine yields the phosphonate compound I-N (equation 1) or thephosphinate compound I-O (equation 2). In addition to the reaction shownfor the synthesis of phosphonates I-N, other methods include the directesterification of a phosphonic acid or the use of the Mitsunobu reaction(Saady et al., Tetrahedron Lett., 1995, 36:2239-2242). The preparationof phosphinic esters of dimethylphosphinic acid (I-O wherein R₉ andR₁₀=Me) has been described using dimethylphosphinyl chloride andtetrazole in the presence of pyridine to produce an intermediatephosphinyl tetrazolide (PCT Intl. Application WO 2000/078763).

Scheme 12 describes the synthesis of compounds of formula I in which

R₄=—(CH₂)_(n)—Z—(CH₂)_(m)—O—PO(OR₇)R₉

and —(CH₂)_(n)Z—(CH₂)_(m)—O—PO—(R₉)R₁₀,

and Z═S or SO₂,

and m=1 or 2,

and n=0, 1 or 2.

Reaction of a suitably activated halogen-substituted heteroaromaticintermediate 8 with potassium thiocyanate gives the thiocyanateintermediate 34. At this point, protecting groups may be removed and theresulting amino heteroaromatic compound coupled with acid 1 usingstandard means such as EDC-HOBt to give intermediate 35. Treatment ofthiocyanate 35 with NaBH₄ yields the corresponding thiol intermediatewhich is alkyated with the substituted halide 36 to give compounds offormula I wherein Z=S(I-P). Treatment of the product I-P with oxidizingagents such as hydrogen peroxide or oxone gives compounds of formula Iwherein Z═SO₂ (I-Q). As an example, treatment of the HBr salt of2-amino-5-bromothiazole (37) with, for instance, potassium thiocyanate,affords thiocyanate 38. The amino-thiocyanate product is acylated withacid 1 using standard means to give the amide 39. Reduction of thethiocyanate group of 39 with a reagent such as NaBH₄, followed byalkylation of the resulting free thiol with iodomethyl phosphonate 40gives phosphonate compounds of formula I where Z═S, m=1 and n=0 (I-P).

Scheme 13 describes the synthesis of compounds of formula I in which

R₄=—(CH₂)_(n)—Z—(CH₂)_(m)—O—PO(OR₇)R₉

and —(CH₂)_(n)Z—(CH₂)_(n)—O—PO—(R₉)R₁₀,

and Z═O,

and m=1 or 2, and n=0, 1 or 2.

Reaction of a suitably activated halogen-substituted heteroaromaticintermediate 41 with the hydroxy substituted phosphonate intermediate 42in the presence of silver oxide yields I-R, the phosphonate compound offormula I in which Z═O, m=1 or 2, and n=0, 1 or 2 (Flor et al., J. Med.Chem., 1999, 42:2633-2640).

Scheme 14 describes a general synthesis of amine 2D, where thephosphonate or phosphinate moiety (here illustrated by a phosphonate) islinked to the heterocycle R1 by a nitrogen atom rather than a carbonatom. A protected (Pro)amino-heterocyle such as 43 can be deprotonatedwith a base followed by alkylation with an appropriate halide containingthe phosphonate/phosphinate moiety followed by deprotection to giveamine 2D. This is illustrated by the example of the N-Boc protectedtriazole 44, which is deprotonated with a base (e.g. NaH), thenalkylated with an iodomethyl phosphonate 45. Deprotection of the N-Bocgroup then furnishes the aminotriazole phosphonate 46. On the otherhand, in certain cases, the amino-heterocycle does not need to beprotected, as illustrated in the case of the pyrazole 47, which can bedeprotonated with a base such as KOtBu and alkylated preferentially onthe ring nitrogen with electrophiles such as an iodomethyl phosphonate45 to form product 48.

An alternative representative approach to N-alkylatedphosphonates/phosphinates is shown in Scheme 15 Amine 43 can bedeprotonated with an appropriate base and reacted with an iodide such as49 (containing a functional group Xa, e.g. Cl, Br, OTs) to give theN-alkylated heterocycle 51. Alternatively, amine can be reacted with aniodide such as 50 (containing e.g., a protected hydroxyl group OP₂,which can subsequently be deprotected and converted to a halide viaknown methods, e.g. Ph₃P/CBr₄) to provide the N-alkylated heterocycle51. This intermediate then can be reacted with either a trialkylphosphate (Arbusov reaction) as described in Scheme 6 to provide aphosphonate, or, as shown here. When halide 51 is reacted with thephosphonite 52, the product is the corresponding phosphinic ester 2E(reference: Kapustin et al., Org. Leu., 2003, 5:3053-3057).

Scheme 16 describes the synthesis of compounds of formula I-S whichcontain cyclic phosphonate esters. The phosphonate diester ofintermediate amine 2F is protected (e.g. as a tert-butyl carbamate or asa benzyl carbamate) to give the phosphonate 53, which is dealkylatedwith an agent such as bromotrimethylsilane. The resultingbis-trimethylsilyl phosphonic acid ester is reacted directly with oxalylchloride to give the phosphoryl dichloride 54. Intermediate 54 isconverted to the desired cyclic phosphonate 55 by reaction with anappropriate diol 54a in the presence of a base (reference: Notter etal., Bioorg. Med. Chem. Lett., 2007, 17:113-117). Deprotection of 55gives the corresponding amine, which is then readily converted tocompounds of formula I-S by the methods previously described in Schemes1 and 2.

Similarly, Scheme 17 describes the synthesis of compounds of formula I-Twhich contain cyclic phosphine oxides. The phosphoryl dichloride 54 canbe reacted with a Grignard reagent formed from a dibromide 56 andmagnesium to provide the cyclic phosphine oxide 57 (ref: R. Polniaszeket. al., J. Org. Chem., 1991, 56:3137-3146). Deprotection of 57 givesthe corresponding amine, which is then converted to compounds of formulaI-T by the methods previously described in Schemes 1 and 2.

Scheme 18 describes the synthesis of compounds of formula I-U whichcontain cyclic phosphinates. Ethyl dichlorophosphate is reacted with aGrignard reagent formed from a dibromide 56 and magnesium to give thecyclic phosphinate ester 58 (ref: R. Polniaszek et. al., J. Org. Chem.,1991, 56:3137-3146). Ester 58 is dealkylated (e.g. withbromotrimethylsilane). The resulting trimethylsilyl phosphonic acidester is reacted directly with a chlorinating agent (e.g. oxalylchloride) to give the phosphoryl chloride 59, which is then reacted withalcohol 31 in the presence of a base to give compounds of formula I-U.

Utilities and Combinations A. Utilities

The compounds of the present invention possess activity as enhancers ofactivity of the enzyme glucokinase, and, therefore, may be used in thetreatment of diseases associated with glucokinase activity.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of diabetes and relatedconditions, microvascular complications associated with diabetes,macrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, and othermaladies. Consequently, it is believed that the compounds of the presentinvention may be used in preventing, inhibiting, or treating diabetes,hyperglycemia, impaired glucose tolerance, insulin resistance,hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed woundhealing, atherosclerosis and its sequelae, abnormal heart function,myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity,dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia,infection, cancer, vascular restenosis, pancreatitis, neurodegenerativedisease, lipid disorders, cognitive impairment and dementia, bonedisease, HIV protease associated lipodystrophy, and glaucoma.

Metabolic Syndrome or “Syndrome X” is described in Ford, et al., J. Am.Med. Assoc., 2002, 287:356-359 and Arbeeny et al., Curr. Med.Chem.—Imm., Endoc. & Metab. Agents, 2001, 1:1-24.

B. Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other enhancers of activity of glucokinase or one or more othersuitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-infective agents,anti-ischemic agents, anti-hypertensive agents, anti-obesity agents,anti-dyslipidemic agents, anti-hyperlipidemic agents,anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents,anti-ischemic agents, anti-cancer agents, anti-cytotoxic agents,anti-restenotic agents, anti-pancreatic agents, lipid lowering agents,appetite suppressants, memory enhancing agents, and cognitive agents.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include insulin and insulinanalogs: LysPro insulin, inhaled formulations comprising insulin;glucagon-like peptides; sulfonylureas and analogs: chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide,glyburide, glimepiride, repaglinide, meglitinide; biguanides: metformin,phenformin, buformin; alpha2-antagonists and imidazolines: midaglizole,isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulinsecretagogues: linogliride, insulinotropin, exendin-4, BTS-67582,A-4166; thiazolidinediones (PPARgamma agonists): ciglitazone,pioglitazone, troglitazone, rosiglitazone; non-thiazolidinedionePPAR-gamma agonists; selective PPARgamma modulators (SPPARMs; e.g.metaglidasen from Metabolex); PPAR-alpha agonists; PPAR alpha/gamma dualagonists; PPAR delta agonists, PPARalpha/gamma/delta pan agonists; SGLT2inhibitors; dipeptidyl peptidase-IV (DPP4) inhibitors; aldose reductaseinhibitors; RXR agonists: JTT-501, MX-6054, DRF2593, LG100268; fattyacid oxidation inhibitors: clomoxir, etomoxir; α-glucosidase inhibitors:precose, acarbose, miglitol, emiglitate, voglibose, MDL-25,637,camiglibose, MDL-73,945; beta-agonists: BRL 35135, BRL 37344, Ro16-8714, ICI D7114, CL 316,243, TAK-667, AZ40140; phosphodiesteraseinhibitors, both cAMP and cGMP type: sildenafil, L686398: L-386,398;amylin antagonists: pramlintide, AC-137; lipoxygenase inhibitors:masoprocal; somatostatin analogs: BM-23014, seglitide, octreotide;glucagon antagonists: BAY 276-9955; insulin signaling agonists, insulinmimetics, PTP1B inhibitors: L-783281, TER17411, TER17529;gluconeogenesis inhibitors: GP3034; somatostatin analogs andantagonists; antilipolytic agents: nicotinic acid, acipimox, WAG 994;glucose transport stimulating agents: BM-130795; glucose synthase kinaseinhibitors: lithium chloride, CT98014, CT98023; and galanin receptoragonists.

Other suitable thiazolidinediones include Mitsubishi's MCC-555(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Wellcome's farglitazar(GI-262570), englitazone (CP-68722, Pfizer), or darglitazone (CP-86325,Pfizer), isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck),R-119702 (Sankyo/WL), N,N-2344 or balaglitazone (Dr. Reddy/NN), orYM-440 (Yamanouchi).

Suitable PPAR alpha/gamma dual agonists include muraglitazar(Bristol-Myers Squibb), tesaglitazar (Astra/Zeneca), naveglitazar(Lilly/Ligand); AVE-0847 (Sanofi-Aventis); TAK-654 (Takeda), as well asthose disclosed by Murakami et al, “A Novel Insulin Sensitizer Acts As aColigand for Peroxisome Proliferation—Activated Receptor Alpha (PPARalpha) and PPAR gamma; Effect of PPAR alpha Activation on Abnormal LipidMetabolism in Liver of Zucker Fatty Rats”, Diabetes 47:1841-1847 (1998),WO 01/21602 and U.S. Pat. No. 6,414,002, the disclosure of which isincorporated herein by reference, employing dosages as set out therein,which compounds designated as preferred are preferred for use herein.Suitable PPARdelta agonists include, for example, GW-501516 (Glaxo).Suitable PPARalpha/gamma/delta pan agonists include, for example,GW-677954 (Glaxo).

Suitable alpha2 antagonists also include those disclosed in WO 00/59506,employing dosages as set out herein.

Suitable SGLT2 inhibitors include T-1095, phlorizin, WAY-123783, andthose described in WO 01/27128.

Suitable DPP4 inhibitors include saxagliptin (Bristol-Myers Squibb),vildagliptin (Novartis) and sitagliptin (Merck) as well as thosedisclosed in WO 99/38501, WO 99/46272, WO 99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO 99/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) as disclosed by Hughes et al, Biochemistry,38(36):11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) asdisclosed by Yamada et al., Bioorg. & Med. Chem. Lett., 8:1537-1540(1998), 2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed byAshworth et al., Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp.1163-1166 and 2745-2748 (1996), employing dosages as set out in theabove references.

Suitable aldose reductase inhibitors include those disclosed in WO99/26659.

Suitable meglitinides include nateglinide (Novartis) or KAD1229(PF/Kissei).

Examples of glucagon-like peptide-1 (GLP-1) include GLP-1(1-36) amide,GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492to Habener), as well as AC2993 (Amylin), and LY-315902 (Lilly).

Other anti-diabetic agents that can be used in combination withcompounds of the invention include ergoset and D-chiroinositol.

Suitable anti-ischemic agents include, but are not limited to, thosedescribed in the Physician's Desk Reference and NHE inhibitors,including those disclosed in WO 99/43663.

Examples of suitable anti-infective agents are antibiotic agents,including, but not limited to, those described in the Physicians' DeskReference.

Examples of suitable lipid lowering agents for use in combination withthe compounds of the present invention include one or more MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, cholesterol ester transfer protein inhibitors (e.g.,torcetrapib (Pfizer)), and/or nicotinic acid and derivatives thereof.

MTP inhibitors which may be employed as described above include thosedisclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat.No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S.Pat. No. 5,885,983, and U.S. Pat. No. 5,962,440.

The HMG CoA reductase inhibitors which may be employed in combinationwith one or more compounds of formula I include mevastatin and relatedcompounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin,(mevinolin) and related compounds, as disclosed in U.S. Pat. No.4,231,938, pravastatin, and related compounds, such as disclosed in U.S.Pat. No. 4,346,227, simvastatin, and related compounds, as disclosed inU.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductaseinhibitors which may be employed herein include, but are not limited to,fluvastatin, disclosed in U.S. Pat. No. 5,354,772; cerivastatin, asdisclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080; atorvastatin, asdisclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and5,686,104; atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), asdisclosed in U.S. Pat. No. 5,011,930; visastatin (Shionogi-Astra/Zeneca(ZD-4522)) as disclosed in U.S. Pat. No. 5,260,440; and related statincompounds disclosed in U.S. Pat. No. 5,753,675; pyrazole analogs ofmevalonolactone derivatives, as disclosed in U.S. Pat. No. 4,613,610;indene analogs of mevalonolactone derivatives, as disclosed in PCTapplication WO 86/03488; 642-(substituted-pyrrol-1-yl)alkyl)pyran-2-onesand derivatives thereof, as disclosed in U.S. Pat. No. 4,647,576;Searle's SC-45355 (a 3-substituted pentanedioic acid derivative)dichloroacetate; imidazole analogs of mevalonolactone, as disclosed inPCT application WO 86/07054; 3-carboxy-2-hydroxy-propane-phosphonic acidderivatives, as disclosed in French Patent No. 2,596,393;2,3-disubstituted pyrrole, furan and thiophene derivatives, as disclosedin European Patent Application No. 0221025; naphthyl analogs ofmevalonolactone, as disclosed in U.S. Pat. No. 4,686,237;octahydronaphthalenes, such as disclosed in U.S. Pat. No. 4,499,289;keto analogs of mevinolin (lovastatin), as disclosed in European PatentApplication No. 0142146 A2; and quinoline and pyridine derivatives, asdisclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin, and ZD-4522.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase, such as those disclosed in GB 2205837, are suitable for usein combination with the compounds of the present invention.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al., J. Med. Chem., 1988, Vol.31, No. 10, pp. 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates, as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design,2:1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20:243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98:1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109:5544 and cyclopropanes reported by Capson, T. L., Ph.D.dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table ofContents, pp. 16, 17, 40-43, 48-51, Summary.

The fabric acid derivatives which may be employed in combination withone or more compounds of formula I include fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like,probucol, and related compounds, as disclosed in U.S. Pat. No.3,674,836, probucol and gemfibrozil being preferred, bile acidsequestrants, such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), EisaiE-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

The ACAT inhibitor which may be employed in combination with one or morecompounds of formula I include those disclosed in Drugs of the Future24:9-15 (1999), (Avasimibe); “The ACAT inhibitor, CI-1011 is effectivein the prevention and regression of aortic fatty streak area inhamsters”, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998),137(1):77-85; “The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB100-containing lipoprotein”,Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1):16-30; “RP73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”,Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1):47-50; “ACATinhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3):204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6):359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd.).

The hypolipidemic agent may be an upregulator of LD2 receptor activity,such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of suitable cholesterol absorption inhibitors for use incombination with the compounds of the invention include SCH48461(Schering-Plough), as well as those disclosed in Atherosclerosis115:45-63 (1995) and J. Med. Chem. 41:973 (1998).

Examples of suitable ileal Na⁺/bile acid cotransporter inhibitors foruse in combination with the compounds of the invention include compoundsas disclosed in Drugs of the Future, 24:425-430 (1999).

The lipoxygenase inhibitors which may be employed in combination withone or more compounds of formula I include 15-lipoxygenase (15-LO)inhibitors, such as benzimidazole derivatives, as disclosed in WO97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones,as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed bySendobry et al “Attenuation of diet-induced atherosclerosis in rabbitswith a highly selective 15-lipoxygenase inhibitor lacking significantantioxidant properties”, Brit. J. Pharmacology (1997) 120:1199-1206, andCornicelli et al, “15-Lipoxygenase and its Inhibition: A NovelTherapeutic Target for Vascular Disease”, Current Pharmaceutical Design,1999, 5:11-20.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g. diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan, and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include a cannabinoid receptor 1antagonist or inverse agonist, a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor beta drug, and/or an anorectic agent.

Cannabinoid receptor 1 antagonists and inverse agonists which may beoptionally employed in combination with compounds of the presentinvention include rimonabant, SLV 319, and those discussed in D. L.Hertzog, Expert Opin. Ther. Patents, 2004, 14:1435-1452.

The beta 3 adrenergic agonists which may be optionally employed incombination with compounds of the present invention include AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer,) or otherknown beta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983, and 5,488,064, with AJ9677, L750,355,and CP331648 being preferred.

Examples of lipase inhibitors which may be optionally employed incombination with compounds of the present invention include orlistat orATL-962 (Alizyme), with orlistat being preferred.

The serotonin (and dopamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of formula I may be sibutramine,topiramate (Johnson & Johnson), or axokine (Regeneron), with sibutramineand topiramate being preferred.

Examples of thyroid receptor beta compounds which may be optionallyemployed in combination with compounds of the present invention includethyroid receptor ligands, such as those disclosed in WO 97/21993 (U. CalSF), WO 99/00353 (KaroBio), and WO 00/039077 (KaroBio), with compoundsof the KaroBio applications being preferred.

The anorectic agent which may be optionally employed in combination withcompounds of the present invention include dexamphetamine, phentermine,phenylpropanolamine, or mazindol, with dexamphetamine being preferred.

Other compounds that can be used in combination with the compounds ofthe present invention include CCK receptor agonists (e.g., SR-27895B);galanin receptor antagonists; MCR-4 antagonists (e.g., HP-228); leptinor mimentics; 11-beta-hydroxysteroid dehydrogenase type-1 inhibitors;urocortin mimetics, CRF antagonists, and CRF binding proteins (e.g.,RU-486, urocortin).

Further, the compounds of the present invention may be used incombination with anti-cancer and cytotoxic agents, including but notlimited to alkylating agents such as nitrogen mustards, alkylsulfonates, nitrosoureas, ethylenimines, and triazenes; antimetabolitessuch as folate antagonists, purine analogues, and pyrimidine analogues;antibiotics such as anthracyclines, bleomycins, mitomycin, dactinomycin,and plicamycin; enzymes such as L-asparaginase; farnesyl-proteintransferase inhibitors; 5α reductase inhibitors; inhibitors of17β-hydroxy steroid dehydrogenase type 3; hormonal agents such asglucocorticoids, estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists,octreotide acetate; microtubule-disruptor agents, such as ecteinascidinsor their analogs and derivatives; microtubule-stabilizing agents such astaxanes, for example, paclitaxel (Taxol®), docetaxel (Taxotere®), andtheir analogs, and epothilones, such as epothilones A-F and theiranalogs; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, taxanes; and topiosomerase inhibitors;prenyl-protein transferase inhibitors; and miscellaneous agents such ashydroxyurea, procarbazine, mitotane, hexamethylmelamine, platinumcoordination complexes such as cisplatin and carboplatin; and otheragents used as anti-cancer and cytotoxic agents such as biologicalresponse modifiers, growth factors; immune modulators; and monoclonalantibodies. Additional anti-cancer agents are disclosed in EP 1177791.The compounds of the invention may also be used in conjunction withradiation therapy.

Examples of suitable memory enhancing agents, anti-dementia agents, orcognitive agents for use in combination with the compounds of thepresent invention include, but are not limited to, donepezil,rivastigmine, galantamine, memantine, tacrine, metrifonate, muscarine,xanomelline, deprenyl, and physostigmine.

The aforementioned patents and patent applications are incorporatedherein by reference.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

The compounds of formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules, or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrasternal injection, or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents.

In carrying out the method of the invention for treating diabetes andrelated diseases, a pharmaceutical composition will be employedcontaining the compounds of formula I, with or without otherantidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or othertype therapeutic agents in association with a pharmaceutical vehicle ordiluent. The pharmaceutical composition can be formulated employingconventional solid or liquid vehicles or diluents and pharmaceuticaladditives of a type appropriate to the mode of desired administration,such as pharmaceutically acceptable carriers, excipients, binders, andthe like. The compounds can be administered to a mammalian patient,including humans, monkeys, dogs, etc. by an oral route, for example, inthe form of tablets, capsules, beads, granules, or powders. The dose foradults is between 0.25 and 2,000 mg per day, preferably between 1 and500 mg, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg), and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

ABBREVIATIONS

The following abbreviations are employed in the Examples and elsewhereherein:

-   Ph=phenyl-   Bn=benzyl-   t-Bu=tertiary butyl-   i-Bu=iso-butyl-   Me=methyl-   Et=ethyl-   Pr=propyl-   iPr=isopropyl-   Bu=butyl-   AIBN=2,2′-Azobisisobutyronitrile-   TMS=trimethylsilyl-   TMSCHN₂=(trimethylsilyl)diazomethane-   TMSN₃=trimethylsilyl azide-   TBS=tert-butyldimethylsilyl-   FMOC=fluorenylmethoxycarbonyl-   Boc or BOC=tert-butoxycarbonyl-   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   THF=tetrahydrofuran-   Et₂O=diethyl ether-   hex=hexanes-   EtOAc=ethyl acetate-   DMF=dimethyl formamide-   MeOH=methanol-   EtOH=ethanol-   DCM=dichloromethane-   i-PrOH=isopropanol-   DMSO=dimethyl sulfoxide-   DME=1,2 dimethoxyethane-   DMA=N,N-dimethylacetylamide-   DCE=1,2 dichloroethane-   HMPA=hexamethyl phosphoric triamide-   HOAc or AcOH=acetic acid-   TFA=trifluoroacetic acid-   DIEA or DIPEA or i-Pr₂NEt or Hunig's Base=diisopropylethylamine-   TEA or Et₃N=triethylamine-   NMM=N-methyl morpholine-   NBS=N-bromosuccinimide-   NCS=N-chlorosuccinimide-   DMAP=4-dimethylaminopyridine-   DEPBT=3-diethoxyphosphoryloxy-1,2,3-benzotriazin-4[3H]-one-   mCPBA=3-chloroperoxybenzoic acid-   NaBH₄=sodium borohydride-   NaBH(OAc)₃=sodium triacetoxyborohydride-   NaN₃=sodium azide-   DIBALH=diisobutyl aluminum hydride-   LiAlH₄=lithium aluminum hydride-   n-BuLi=n-butyllithium-   Oxone®=monopersulfate-   Pd/C=palladium on carbon-   PXPd₂=Dichloro(chlorodi-tert-butylphosphine)palladium (II) dimer or    [PdCl₂(t-Bu)₂PCl]₂-   PtO₂=platinum oxide-   KOH=potassium hydroxide-   NaOH=sodium hydroxide-   LiOH=lithium hydroxide-   LiOH.H₂O=lithium hydroxide monohydrate-   HCl=hydrochloric acid-   H₂SO₄=sulfuric acid-   H₂O₂=hydrogen peroxide-   Al₂O₃=aluminum oxide-   K₂CO₃=potassium carbonate-   Cs₂CO₃=cesium carbonate-   NaHCO₃=sodium bicarbonate-   ZnBr₂=zinc bromide-   MgSO₄=magnesium sulfate-   Na₂SO₄=sodium sulfate-   KSCN=potassium thiocyanate-   NH₄Cl=Ammonium chloride-   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene-   EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or    EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or    1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)-   HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate-   HOAT=1-Hydroxy-7-azabenzotriazole-   PyBOP reagent or BOP    reagent=benzotriazol-1-yloxy-tris(dimethylamino) phosphonium    hexafluorophosphate-   NaN(TMS)₂=sodium hexamethyldisilazide or sodium    bis(trimethylsilyl)amide-   Ph₃P=triphenylphosphine-   Pd(OAc)₂=Palladium acetate-   (Ph₃P)₄Pd^(o)=tetrakis triphenylphosphine palladium-   Pd₂(dba)₃=tris(dibenzylacetone)dipalladium-   DPPF=1,1′-Bis(diphenylphosphino)ferrocene-   HATU=2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate,    2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate(V)-   DEAD=diethyl azodicarboxylate-   DIAD=diisopropyl azodicarboxylate-   Cbz-C1=benzyl chloroformate-   CAN=ceric ammonium nitrate-   SAX=Strong Anion Exchanger-   SCX=Strong Cation Exchanger-   H₂=hydrogen-   Ar=argon-   N₂=nitrogen-   Equiv=equivalent(s)-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   meq=milliequivalent-   RT or R.T.=room temperature-   AT=ambient temperature-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   HPLC R_(t)═HPLC retention time-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NMR=nuclear magnetic resonance-   NMR spectral data: s=singlet; d=doublet; m=multiplet; br=broad;    t=triplet-   mp=melting point

EXAMPLES

The following working Examples serve to better illustrate, but notlimit, some of the preferred embodiments of the present invention.

General

The term HPLC refers to a Shimadzu high performance liquidchromatography with one of following methods:

Method A: YMC or Phenomenex C18 5 micron 4.6×50 mm column using a 4minute gradient of 0-100% solvent B [90% MeOH:10% H₂O:0.2% H₃PO₄] and100-0% solvent A [10% MeOH:90% H₂O:0.2% H₃PO₄] with 4 mL/min flow rateand a 1 min. hold, an ultra violet (uv) detector set at 220 nm.

Method B: Phenomenex S5 ODS 4.6×30 mm column, gradient elution 0-100%B/A over 2 min (solvent A=10% MeOH/H₂O containing 0.1% TFA, solventB=90% MeOH/H₂O containing 0.1% TFA), flow rate 5 mL/min, UV detection at220 nm.

Method C: YMC S7 ODS 3.0×50 mm column, gradient elution 0-100% B/A over2 min (solvent A=10% MeOH/H₂O containing 0.1% TFA, solvent B=90%MeOH/H₂O containing 0.1% TFA), flow rate 5 mL/min, UV detection at 220nm.

The term prep HPLC refers to an automated Shimadzu HPLC system using amixture of solvent A (10% MeOH/90% H₂O/0.2% TFA) and solvent B (90%MeOH/10% H₂O/0.2% TFA). The preparative columns are packed with YMC orPhenomenex ODS C18 5 micron resin or equivalent.

The following Examples are illustrative of preferred compounds of theinvention.

Example 1

Trimethylacetyl chloride (3.83 mL; 31.1 mmol) was added dropwise to a−10° C. mixture of 4-methylthio-phenylacetic acid (5.40 g; 29.6 mmol)and K₂CO₃ (12.3 g; 88.8 mmol) in acetone (40 mL), while maintaining thetemperature at <−10° C. After 10 min at −10° C., the reaction was warmedto 0° C. After 10 min at 0° C., the reaction was cooled to −10° C.(1R,2R)-(−)-pseudoephedrine (7.34 g; 44.4 mmol) was added. After 10 minat −10° C., the reaction mixture was allowed to warm to RT. After 4 h,the reaction was partitioned between EtOAc (60 mL) and H₂O (30 mL).

The aqueous phase was extracted with EtOAc (30 mL). All organic phaseswere combined, washed with brine (30 mL), dried (MgSO₄) and concentratedin vacuo. The crude product was recrystallized from warm EtOAc/hexanesto afford Part A compound (7.3 g; 75%) as a crystalline solid.

A solution of Part A compound (7.0 g; 21.27 mmol) in THF (51 mL) wasadded over 45 min to a −70° C. solution of LiN(TMS)₂ (44.7 mL of a 1.0 Msolution in THF; 44.7 mmol) while keeping the internal temperature below−65° C. After addition the reaction mixture was stirred at −70° C. for15 min and then allowed to warm to 0° C. After 20 min at 0° C. thereaction was re-cooled to −70° C. A solution of cyclopentylmethyl iodide(6.70 g; 31.91 mmol) in DMPU (5.4 mL; 44.68 mmol) was added. Thereaction was stirred at −70° C. for 30 min and then allowed to warm toRT. After 20 h the reaction mixture was quenched by addition of sat.aqueous NH₄Cl (20 mL). The solution was extracted with EtOAc (175 mL).The organic phase was isolated, washed with sat. NH₄Cl (50 mL) and brine(50 mL), dried (MgSO₄) and concentrated. The crude product was purifiedby flash chromatography (SiO₂; continuous gradient from 0 to 90% solventB over 75 min, where solvent A=hexanes and solvent B=EtOAc) to give PartB compound (6.94 g; 79%).

A solution of Part B compound (5.44 g; 13.22 mmol) in 1,4 dioxane (24mL) was treated with 9 N aqueous H₂SO₄ (15 mL). The reaction mixture wasthen heated at 105° C. After 20 h heating was stopped and the solutionwas cooled to RT. H₂O (100 mL) was added to precipitate the product. Thesolid was isolated by filtration and dried in vacuo to give Part Ccompound (3.40 g; 97%).

Oxone® (17.64 g; 28.70 mmol) was added to a mixture of Part C compound(3.30 g; 12.48 mmol) in 2-propanol (90 mL) and H₂O (45 mL). After 20 hat RT the 2-propanol was removed in vacuo. The aqueous solution wasextracted with EtOAc (175 mL). The organic phase was washed with H₂O (50mL) and brine (50 mL), dried (MgSO₄) and concentrated in vacuo to givePart D compound (3.60 g; 97%) as a white solid. (Part D compound wasprepared by a slight modification of the procedure found in Patent WO02/46173).

Di-tert-butyl dicarbonate (2.40 g; 11.00 mmol) was added to a solutionof 2-aminothiazole (1.00 g; 9.99 mmol) in THF (5 mL). TEA (1.67 mL;11.98 mmol) was added followed by a catalytic amount of 4-DMAP (2.0 mg).After 4 h the reaction mixture was concentrated in vacuo. The residuewas partitioned between EtOAc (20 mL) and 0.1 N aqueous HCl (15 mL). Theorganic phase was washed with brine (15 mL), dried (MgSO₄) andconcentrated in vacuo. The crude product was chromatographed (SiO₂;continuous gradient from 0 to 100% solvent B over 25 min; hold at 100%solvent B for 5 min, where solvent A=hexanes and solvent B=EtOAc) togive Part E compound (0.77 g; 39%) as a white solid.

A −78° C. solution of LDA (1.44 mL of a 2.0 M solution inTHF/heptane/ethylbenzene; 2.88 mmol) was cannulated into a −78° C.solution of Part A compound (0.25 g; 1.25 mmol) in THF (4 mL). After 30min a solution of ClPO₃Et₂ (270 μL; 1.87 mmol) in THF (0.5 mL) wasslowly added. The reaction mixture was allowed to slowly warm to RTovernight. After 16 h the reaction was quenched by addition of H₂O (0.5mL). The solution was partitioned between EtOAc (5 mL) and brine (5 mL).The organic phase was dried (MgSO₄) and concentrated in vacuo. The crudeproduct chromatographed (SiO₂; continuous gradient from 0 to 100%solvent B over 10 min, hold at 100% solvent B for 10 min, where solventA=hexanes and solvent B=EtOAc) to give Part F compound (0.12 g; 29%).

TFA (0.40 mL) was added to a 0° C. solution of Part B compound (0.12 g;0.37 mmol) in DCM (0.80 mL). After addition was complete the reactionmixture was allowed to warm to RT and stirred at RT for 4 h. Volatileswere removed in vacuo, and the residue was dissolved in EtOAc (3 mL).The EtOAc solution was washed with sat. aqueous NaHCO₃ (3 mL). Theaqueous layer was extracted with EtOAc (2 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to give Part Gcompound (83.0 mg; 96%).

DEPBT (47.8 mg; 0.16 mmol) was added to a solution of Part D compound(23.7 mg; 0.08 mmol) and Part G compound (20.8 mg; 0.09 mmol) in THF(0.40 mL). DIPEA (27.0 uL; 0.16 mmol) was added. After 24 h at RT thereaction mixture was concentrated in vacuo. The residue was dissolved inEtOAc (3 mL). The EtOAc layer was washed with 1 N aqueous HCl (2 mL),H₂O (2 mL), sat. aqueous NaHCO₃ (2×2 mL) and brine (2 mL), dried (MgSO₄)and concentrated in vacuo. The crude product was dissolved in DCM (3mL). The solution was stirred with aminomethylated polystyrene resin (40mg; to remove unreacted activated ester) for 20 min and then filtered.The filtrate was concentrated in vacuo. The residue was purified bypreparative HPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flowrate=40 mL/min, 10 to 100% solvent B over 12 min, hold to 16 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to give the title compound (15 mg; 37%) as a colorless solid.[M+H]⁺=515.2; ¹H NMR (400 MHz, CD₃OD): δ 1.19 (m, 2H), 1.33 (m, 6H),1.50 (m, 2H), 1.64 (m, 3H), 1.80 (m, 2H), 1.89 (m, 1H), 2.23 (m, 1H),3.10 (s, 3H), 4.00 (t, 1H), 4.12 (m, 4H), 7.69 (d, 2H), 7.89 (d, J=4.8Hz, 1H), 7.93 (d, 2H).

Example 2

Oxalyl chloride (2.0 M in DCM) (0.68 mL; 1.35 mmol) was added to amixture of Example 1 Part D compound (200 mg; 0.68 mmol) in DCM (1 mL).DMF (5 μL) was added. Gas evolution occurred. After 2 h at RT thereaction mixture was concentrated in vacuo. The residue was strippedfrom CHCl₃ (2×2 mL), then was dissolved in DCM (2.5 mL). The solutionwas cooled to 0° C. and 2-amino-5-bromopyridine (175 mg; 1.01 mmol) wasadded followed by pyridine (82 uL; 1.01 mmol). The reaction mixture wasstirred at RT for 16 h, then was concentrated in vacuo. The residue waspartitioned between EtOAc (5 mL) and 0.1 N aqueous HCl (4 mL). Theorganic phase was washed with brine (4 mL), dried (MgSO₄), andconcentrated in vacuo. The crude product was chromatographed (SiO₂;continuous gradient from 0 to 80% solvent B over 18 min, where solventA=hexanes and solvent B=EtOAc) to give Part A compound (250 mg; 82%).

THF (degassed) (0.50 mL) was added to Part A compound (28.9 mg; 0.064mmol) and (Ph₃P)₄Pd^(o) (14.8 mg; 0.013 mmol). H(O)P(OEt)₂ (10.3 μL;0.079 mmol) was added followed by TEA (13.7 μL; 0.098 mmol). The vesselwas capped and the reaction mixture was heated at 75° C. for 9 h, thenwas cooled to RT and concentrated in vacuo. The crude product waspurified by preparative HPLC(YMC reverse phase ODS-A-5 u 30×100 mmcolumn; flow rate=40 mL/min, 20 to 100% solvent B over 12 min, hold at100% solvent B for 17 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA andsolvent B=90:10:0.1 MeOH:H₂O:TFA) to give title compound (18 mg; 55%) asan amorphous solid. [M+H]⁺=509.2; ¹H NMR (400 MHz, CD₃OD): δ 1.19 (m,2H), 1.32 (t, 6H), 1.51 (m, 2H), 1.64 (m, 3H), 1.84 (m, 3H), 2.22 (m,1H), 3.09 (s, 3H), 4.02 (t, 1H), 4.12 (m, 4H), 7.70 (d, 2H), 7.92 (d,2H), 8.08 (ddd, 1H), 8.26 (dd, 1H), 8.60 (dd, 1H).

Example 3

The title compound (14.3 mg; 44%; yellow amorphous solid) wassynthesized from 5-bromo-2-pyrazinamine employing the proceduredescribed in Example 2. [M+H]⁺=510.2; ¹H NMR (400 MHz, CD₃OD): δ 1.19(m, 2H), 1.33 (t, 6H), 1.51 (m, 2H), 1.64 (m, 3H), 1.84 (m, 3H), 2.22(m, 1H), 3.09 (s, 3H), 4.03 (t, 1H), 4.21 (m, 4H), 7.71 (d, 2H), 7.92(d, 2H), 8.71 (s, 1H), 9.59 (s, 1H).

Example 4

CH₃CN (150 μL) was added to a mixture of Example 2 Part A compound (30mg; 0.066 mmol), Pd(OAc)₂ (0.30 mg; 0.0013 mmol) andtri-o-tolylphosphine (0.80 mg; 0.0026 mmol). Diethyl vinylphosphate(10.7 uL; 0.083 mmol) was added followed by TEA (27.7 uL; 0.199 mmol).The reaction mixture was heated at 95° C. for 4 h, then was cooled toRT. The solution was partitioned between EtOAc (3 mL) and brine (2 mL).The organic phase was dried (MgSO₄) and concentrated in vacuo. Theresidue was chromatographed (SiO₂; continuous gradient from 0 to 100%solvent B over 12 min, hold at 100% for 8 min, where solvent A=hexanesand solvent B=EtOAc) to give the title compound (24 mg; 68%) as anamorphous solid. [M+H]⁺=535.3; ¹H NMR (400 MHz, CDCl₃): δ 1.15 (m, 2H),1.36 (t, 6H), 1.48 (m, 2H), 1.61 (m, 3H), 1.74 (m, 2H), 1.92 (m, 1H),2.23 (m, 1H), 3.05 (s, 3H), 3.68 (t, 1H), 4.14 (m, 4H), 6.25 (t, 1H),7.42 (d, J=22.4 Hz, 2H), 7.59 (d, 2H), 7.85 (dd, 1H), 7.92 (d, 2H), 8.23(s, 1H), 8.24 (d, 2H), 8.31 (d, 1H).

Example 5

10% Pd/C (5 mg) was added to a solution of Example 4 compound (20 mg;0.037 mmol) in MeOH (0.30 mL). A H₂ atmosphere was introduced viaballoon. After 8 h the reaction mixture was filtered. The catalyst wasrinsed with MeOH (1.5 mL) and the combined filtrates were concentratedin vacuo. The crude product was chromatographed (SiO₂; continuousgradient from 0 to 100% solvent B over 6 min, hold at 100% solvent B for15 min, where solvent A=hexanes and solvent B=EtOAc) to give the titlecompound (14.5 mg; 73%) as a colorless solid. [M+H]⁺=537.2; ¹H NMR (400MHz, CDCl₃): δ 1.13 (m, 2H), 1.31 (t, 6H), 1.47 (m, 2H), 1.61 (m, 2H),1.74 (m, 3H), 1.90 (m, 1H), 2.00 (m, 2H), 2.21 (m, 1H), 2.87 (m, 2H),3.05 (s, 3H), 3.65 (t, 1H), 4.10 (m, 4H), 7.56 (dd, 1H), 7.58 (d, 2H),7.90 (d, 2H), 8.08 (d, 1H), 8.13 (d, 1H), 8.20 (s, 1H).

Example 6

To a 0° C. solution of(S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydroisoindol-2-yl)-propionic acid (144mg, 0.5 mmol, prepared as described in WO 2002/048106) and oxalylchloride (0.38 mL of a 2 M solution in DCM; 0.75 mmol) in DCM (1 mL)under Ar was added DMF (1 drop). After 30 min, the reaction was allowedto warm to RT and was stirred at RT for 4 h. Volatiles were removed invacuo; the crude acid chloride was re-dissolved in DCM (3 mL).5-Bromo-2-aminopyrazine (130 mg, 0.75 mmol) and pyridine (0.061 mL, 0.75mmol) were added to the acid chloride solution cooled in an ice bathunder Ar. The reaction mixture was allowed to warm to room temperatureovernight, then was diluted with DCM (6 mL) and rinsed with 0.5 Naqueous HCl (1 mL, 2×), water (1 mL), sat. aqueous NaHCO₃ (1 mL), brine(1 mL), then dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (40 g SiO₂, 0-50% EtOAc-hexanes gradient) gave 188 mg(84%) of racemic Part A compound.

THF (degassed) (0.40 mL) was added to a reaction flask containing Part Acompound (25.0 mg; 0.056 mmol) and (Ph₃P)₄Pd(0)(12.9 mg; 0.011 mmol).Diethyl phosphite (8.72 uL; 0.068 mmol) was added followed by TEA (10.9uL; 0.078 mmol). The reaction vessel was capped and the reaction mixturewas heated at 85° C. for 6 h, then cooled to RT and concentrated invacuo. The residue was partitioned between EtOAc (2 mL) and brine (1.5mL). The organic phase was isolated, dried (MgSO₄) concentrated invacuo. The crude product was purified by preparative HPLC(YMC reversephase ODS-A-5 u 30×100 mm column; flow rate=40 mL/min., 45 to 100%solvent B over 12 min, hold to 16 min, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to give titlecompound (8 mg; 29%; colorless solid) as a racemic mixture.[M+H]⁺=501.3; ¹H NMR (400 MHz, CDCl₃): δ 1.00 (m, 2H), 1.20 (m, 4H),1.35 (m, 6H), 1.65 (m, 3H), 1.85 (m, 3H), 2.05 (m, 1H), 4.22 (m, 4H),4.54 (q, 2H), 5.23 (t, 1H), 7.50 (m, 3H), 7.60 (dd, 1H), 7.92 (d, 1H),8.75 (s, 1H), 9.52 (s, 1H), 9.62 (s, 1H).

Example 7

(EtO)₃P (0.60 mL; 3.47 mmol) was added to a reaction flask containing asolution of tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (Bioorg.Med. Chem. Lett., 2002, 12:1203-1208) (125 mg; 0.434 mmol) in THF (1.0mL). The reaction vessel was capped and the reaction mixture was heatedat 80° C. for 16 h, then was cooled to RT and concentrated in vacuo. Thecrude product was chromatographed (SiO₂; continuous gradient from 0 to100% solvent B over 8 min, hold at 100% solvent B for 8 min, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (145 mg;96%).

TFA (0.30 mL) was added to a cold (0° C.) solution of Part A compound(144 mg; 0.417 mmol) in DCM (1.2 mL). The reaction mixture was thenstirred at RT for 16 h, then was concentrated in vacuo. The residue waspartitioned between EtOAc (4 mL) and sat. aqueous NaHCO₃ (3 mL). Theorganic phase was isolated, washed with brine (3 mL), dried (MgSO₄), andconcentrated in vacuo to give Part B compound (51 mg; 50%).

Oxalyl chloride (0.84 uL of a 2.0 M solution in DCM; 0.168 mmol) wasadded to a mixture of Example 1 Part D compound (25 mg; 0.084 mmol) inDCM (0.15 mL). DMF (5 μL) was added. Gas evolution occurred. After 1.5 hat RT the reaction mixture was concentrated in vacuo. The residue wasstripped from CHCl₃ (2×0.8 mL). The crude acid chloride was thendissolved in DCM (0.25 mL). Part B compound (24.8 mg; 0.101 mmol) wasadded followed by pyridine (10.2 uL; 0.126 mmol). After stirring for 16h at RT the reaction was concentrated in vacuo. The residue waspartitioned between EtOAc (4 mL) and brine (2 mL). The organic phase wasdried (MgSO₄) and concentrated in vacuo. The crude product was purifiedby preparative HPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flowrate=40 mL/min, 10 to 100% solvent B over 12 min, hold to 16 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to give the title compound (18 mg; 41%) as an amorphous solid.[M+H]⁺=524.4; ¹H NMR (400 MHz, CD₃OD): δ 1.18 (m, 2H), 1.27 (t, 6H),1.51 (m, 2H), 1.64 (m, 2H), 1.72 (m, 1H), 1.83 (m, 3H), 2.22 (m, 1H),3.09 (s, 3H), 3.46 (d, 2H), 4.00 (t, 1H), 4.09 (m, 4H), 7.70 (d, 2H),7.92 (d, 2H), 8.32 (s, 1H), 9.30 (s, 1H).

Example 8

The title compound (11 mg; 19%; colorless solid) was synthesized fromtrimethylphosphite employing the sequence described for the synthesis ofExample 7. [M+H]⁺=496.3; ¹H NMR (400 MHz, CD₃OD): δ 1.19 (m, 2H), 1.51(m, 2H), 1.64 (m, 2H), 1.72 (m, 1H), 1.84 (m, 3H), 2.23 (m, 1H), 3.09(s, 3H), 3.50 (d, 2H), 3.73 (s, 3H), 3.76 (s, 3H), 4.00 (t, 1H), 7.69(d, 2H), 7.91 (d, 2H), 8.31 (s, 1H), 9.29 (s, 1H).

Example 9

A solution of bromine (145 uL; 2.82 mmol) in CCl₄ (5 mL) was addeddropwise to a 0° C. solution of acetyl-phosphonic acid di-ethyl ester(0.508 g; 2.82 mmol) in CCl₄ (5 mL). The reaction mixture was thenstirred at RT for 2 h, then was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 0 to 100% solvent B over10 min, hold at 100% solvent B for 10 min, where solvent A=hexanes andsolvent B=EtOAc) to give Part A compound (250 mg; 34%).

Thiourea (43.9 mg; 0.577 mmol) was added to a solution of Part Acompound (135 mg 0.52 mmol) in EtOH (1.0 mL). The reaction mixture wasstirred at RT for 48 h, then was concentrated in vacuo. The residue waspartitioned between EtOAc (5 mL) and sat. aqueous NaHCO₃ (3 mL). Theorganic phase was isolated, washed with brine (3 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 0 to 100% solvent B over 2 min, hold at 100% solvent B for10 min, where solvent A=hexanes and solvent B=EtOAc) to give Part Bcompound (22 mg; 18%).

DEPBT (50 mg; 0.168 mmol) was added to a stirred solution of Example 1Part D compound (25 mg; 0.084 mmol) and Part B compound (21.9 mg; 0.093mmol) in THF (0.40 mL). DIPEA (28.4 uL; 0.168 mmol) was added. After 96h at RT the reaction mixture was concentrated in vacuo. The residue wasdissolved in EtOAc (3 mL). The EtOAc solution was washed with brine (2mL), dried (MgSO₄), filtered, and concentrated in vacuo. The crudeproduct was purified by preparative HPLC(YMC reverse phase ODS-A-5 u30×100 mm column; flow rate=40 mL/min, 20 to 100% solvent B over 12 min,hold to 15 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA) to give title compound (13 mg; 30%) as a whitesolid. [M+H]⁺=515.2; ¹H NMR (400 MHz, CD₃OD): δ 1.18 (m, 2H), 1.31 (m,6H), 1.51 (, 2H), 1.64 (m, 3H), 1.81 (m, 2H), 1.88 (m, 1H), 2.23 (m,1H), 3.10 (s, 3H), 3.96 (t, 1H), 4.14 (m, 4H), 7.68 (d, 2H), 7.86 (d,J=4.95 Hz, 1H), 7.93 (d, 2H).

Example 10

DEPBT (162 mg; 0.540 mmol) was added to a stirred solution of Example 1Part D compound (80 mg; 0.270 mmol) and 2-amino-6-bromopyridine (51.4mg; 0.297 mmol) in THF (1.0 mL). DIPEA (91.0 uL; 0.540 mmol) was added.After 48 h at RT more 2-amino-6-bromopyridine (93.0 mg; 0.537 mmol) wasadded. After an additional 48 h the reaction mixture was concentrated invacuo. The residue was partitioned between EtOAc (6 mL) and 0.1 Naqueous HCl (3 mL). The organic phase was washed with brine (3 mL),dried (MgSO₄) and concentrated in vacuo. The crude product was purifiedby preparative HPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flowrate=40 mL/min, 35 to 100% solvent B over 10 min, hold to 13 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to give Part A compound (16 mg; 13%).

THF (degassed) (0.50 mL) was added to a reaction flask containing Part Acompound (14.0 mg; 0.031 mmol) and (Ph₃P)₄Pd(0)(7.2 mg; 0.006 mmol).Diethyl phosphite (4.8 uL; 0.037 mmol) was added followed by Et₃N (6.0μL; 0.043 mmol). The reaction vessel was capped and the reaction mixturewas heated at 75° C. for 12 h, then was cooled to RT. The reactionmixture was concentrated in vacuo. The crude product was purified bypreparative HPLC(YMC reverse phase ODS-A-5 u 20×100 mm column; flowrate=40 mL/min., 20 to 100% solvent B over 12 min, hold to 15 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to give the title compound (3.6 mg; 23%) as a colorless solid.[M+H]⁺=509.3; ¹H NMR (400 MHz, CD₃OD): δ 1.20 (m, 2H), 1.33 (m, 6H),1.53 (m, 2H), 1.65 (m, 2H), 1.72 (m, 1H), 1.83 (m, 3H), 2.22 (m, 1H),3.09 (s, 3H), 4.01 (t, 1H), 4.19 (m, 4H), 7.61 (t, 1H), 7.71 (d, 2H),7.91 (m, 3H), 8.32 (d, 1H).

Example 11

To a 0° C. mixture of 4-methylsulfonylaniline, hydrochloride (1.06 g,5.10 mmol), cyclopentane carboxaldehyde (0.5 g, 5.10 mmol), and Et₃N (1mL, 7.14 mmol) in 20 mL of dichloroethane was added NaBH(OAc)₃ (1.51 g,7.14 mmol). The reaction was allowed to warm to RT and stirred at RT fortwo days, then was treated with excess sat. aqueous NaHCO₃. The aqueouslayer was extracted with EtOAc. The organic extract was rinsed withbrine, dried (MgSO₄) and concentrated in vacuo. Purification by flashchromatography (120 g silica gel, continuous gradient from 0-100%EtOAc-hexanes) gave Part A compound (904 mg, 70% yield).

Part 1: 4-Nitrophenylchloroformate (49.3 mg; 0.245 mmol) was added to acold (0° C.) solution of Example 7 Part B compound (60 mg; 0.245 mmol).Pyridine 20.8 μL; 0.257 mmol) was added. The reaction mixture wasstirred at RT for 1 h, then was concentrated in vacuo to give the crudecarbamate.

Part 2: The crude carbamate was dissolved in CH₃CN (1.0 mL). Part Acompound (62 mg; 0.245 mmol) was added. The reaction mixture was heatedat 40° C. for 2 h, then was cooled to RT and concentrated in vacuo. Thecrude product was chromatographed (SiO₂; continuous gradient from 0 to100% solvent B over 4 min, switch to solvent C, hold at 100% solvent Cfor 8 min, where solvent A=hexanes, solvent B=EtOAc and solvent C=10%MeOH in EtOAc) to give title compound (30 mg; 23%—two steps) as anamorphous solid. [M+H]⁺=525.3; ¹H NMR (400 MHz, CD₃OD): δ 1.28 (t, 8H),1.54 (m, 2H), 1.67 (m, 4H), 2.10 (m, 1H), 3.17 (s, 3H), 3.45 (d, 2H),3.83 (d, 2H), 4.09 (m, 4H), 7.65 (d, 2H), 8.05 (d, 2H), 8.19 (s, 1H),9.12 (s, 1H).

Example 12

DIPEA (8.05 mL; 46.24 mmol) was added to a cold (0° C.) solution of2-amino-5-picoline (2.50 g; 23.12 mmol) in DCM (30 mL). A solution ofdi-tert-butyl dicarbonate (12.61 g; 57.80 mmol) in DCM (17 mL) was addedfollowed by 4-DMAP (2.82 g; 23.12 mmol). The reaction mixture was thenstirred at RT for 16 h, then was concentrated in vacuo to half volume.The solution was diluted with EtOAc (125 mL). The organic solution waswashed with sat. aqueous NH₄Cl (3×45 mL), brine (45 mL), sat. aqueousNaHCO₃ (2×45 mL) and brine (45 mL). The solution was then dried (MgSO₄)and concentrated in vacuo. The crude product was chromatographed (SiO₂;continuous gradient from 15 to 20% EtOAc in hexanes) to give Part Acompound (2.70 g; 38%).

N-bromosuccinimide (1.56 g; 8.76 mmol) was added to a solution of Part Acompound (2.70 g; 8.76 mmol) in CCl₄ (40 mL). Benzoyl peroxide (0.21 g;0.88 mmol) was added. The reaction mixture was heated to reflux (80° C.)for 7 h, then was cooled to RT. The reaction mixture was filtered andthe filtrate was concentrated in vacuo. The crude product waschromatographed (SiO₂; 5% EtOAc in DCM) to give Part B compound (1.48 g;44%). (Bioorg. Med. Chem. Lett, 2004, 14:2227-2231).

Triethylphosphite (1.2 mL; 6.97 mmol) was added to a solution of Part Bcompound (0.45 g; 1.16 mmol) in THF (2.5 mL). The reaction vessel wascapped and the reaction mixture was heated at 80° C. for 16 h, then wascooled to RT. The solution was concentrated in vacuo. The crude productwas chromatographed (SiO₂; continuous gradient from 0 to 100% solvent Bover 8 min, hold at 100% solvent B for 6 min, where solvent A=hexanesand solvent B=EtOAc) to give Part C compound (0.52 g; 100%).

TFA (1.5 mL) was added to a cold (0° C.) solution of Part C compound(0.52 g; 1.17 mmol) in DCM (3 mL). The reaction mixture was then stirredat RT for 3 h, then was concentrated in vacuo. The residue waspartitioned between CHCl₃ (10 mL) and sat. aqueous NaHCO₃ (8 mL). Theaqueous phase was extracted with CHCl₃ (8 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to give Part Dcompound (0.25 g; 88%).

Oxalyl chloride (2.0 M in DCM) (104 μL; 0.208 mmol) was added to a 0° C.solution of Example 1 Part D compound (30.9 mg; 0.104 mmol) in DCM (0.3mL). DMF (5 μL) was added. Gas evolution occurred. After 1 h at RT thereaction mixture was concentrated in vacuo. The residue was strippedfrom CHCl₃ (2×1 mL). The crude acid chloride was dissolved in DCM (0.42mL). Part D compound (25.5 mg; 0.104 mmol) was added followed bypyridine (12.6 uL; 0.156 mmol). After stirring for 16 h the reaction wasconcentrated in vacuo. The residue was partitioned between EtOAc (5 mL)and brine (4 mL). The organic phase was dried (MgSO₄) and concentratedin vacuo. The crude product was purified by preparative HPLC(YMC reversephase ODS-A-5 u 30×100 mm column; flow rate=40 mL/min, 20 to 100%solvent B over 15 min, hold to 20 min, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to give the titlecompound (19 mg; 34%) as an amorphous solid. [M+H]⁺=523.4; ¹H NMR (400MHz, CD₃OD): δ 1.20 (m, 2H), 1.27 (t, 6H), 1.51 (m, 2H), 1.65 (m, 2H),1.71 (m, 1H), 1.85 (m, 3H), 2.21 (m, 1H), 3.10 (s, 3H), 3.30 (d, 2H),3.98 (t, 1H), 4.07 (m, 4H), 7.70 (d, 2H), 7.92 (m, 4H), 8.23 (s, 1H).

Example 13

A solution of di-tert-butyl dicarbonate (11.3 g; 51.83 mmol) in THF (50mL) was added to a cold (0° C.) solution of ethyl2-aminothiazole-4-carboxylate (8.59 g; 49.36 mmol) in THF (150 mL). TEA(7.57 mL; 54.30 mmol) was added followed by a catalytic amount of 4-DMAP(30 mg). The reaction mixture was stirred at RT for 16 h, then wasconcentrated in vacuo. The residue was portioned between EtOAc (300 mL)and 0.5 N aqueous HCl (250 mL). The organic phase was washed with brine(150 mL), dried (MgSO₄) and concentrated in vacuo to give Part Acompound (12.38 g; yield given below in Part B). The crude product wasused in the next step without further purification.

A solution of LiAlH₄ (1.0 M in THF) (48.0 mL; 48.0 mmol) was added to acold (0° C.) solution of Part A compound (12.38 g; 45.3 mmol) in THF(130 mL). After 3 h at 0° C. the reaction was carefully quenched bydropwise addition of H₂O (5 mL). After 10 min, 5 N aqueous NaOH (2.5 mL)was added. After another 10 min, the solution was concentrated in vacuo.The residue was partitioned between EtOAc (300 mL) and H₂O (200 mL). Theaqueous phase was extracted with EtOAc (100 mL). The combined organicphases were dried (MgSO₄) and concentrated in vacuo. The crude productwas chromatographed (SiO₂; continuous gradient from 0 to 100% solvent Bover 16 min, hold at 100% solvent B for 5 min, where solvent A=hexanesand solvent B=EtOAc) to give Part B compound (8.67 g; 67%—two steps).

Method 1: A solution of methanesulfonyl chloride (318 μL; 4.10 mmol) inDCM (3 mL) was slowly added to a 0° C. solution of Part B compound (900mg; 3.91 mmol) and TEA (600 μL; 4.30 mmol) in DCM (10 mL). After 25 minof stirring the reaction mixture was diluted with acetone (13 mL). LiBr(2.03 g; 23.46 mmol) was added. The reaction was stirred at RT for 1 h,then was diluted with sat. aqueous NH₄Cl (20 mL) and extracted with Et₂O(2×40 mL). The combined organic extracts were washed with sat. aqueousNH₄Cl (2×20 mL) and brine (20 mL). The solution was dried (MgSO₄) andconcentrated in vacuo to give Part C compound (1.03 g; 89%). The crudeproduct was taken forward without further purification.

Method 2: N-Boc thiourea (428 mg; 2.427 mmol) was added to a solution of1,3-dibromoacetone (524 mg; 2.427 mmol) in acetone (9.7 mL). After 24 hat RT the reaction mixture was concentrated in vacuo to give Part Ccompound (0.78 g; Quant.) as a brown foam. The crude product was takenforward without further purification.

Triethyl phosphite (3.6 mL; 20.96 mmol) was added to a solution of PartC compound (878 mg; 2.99 mmol) in THF (6 mL). The reaction vessel wascapped and the reaction mixture was heated at 80° C. for 16 h, then wascooled to RT. The solution was concentrated in vacuo. The crude productwas chromatographed (SiO₂; continuous gradient from 0 to 100% solvent Bover 8 min, hold at 100% solvent B for 10 min, where solvent A=hexanesand solvent B=EtOAc) to give Part D compound (0.86 g; 82%).

TFA (3.0 mL) was added to a 0° C. solution of Part D compound (0.86 g;2.45 mmol) in DCM (7 mL). The reaction mixture was stirred at RT for 2.5h, then was concentrated in vacuo. The residue was partitioned betweenEtOAc (15 mL) and sat. aqueous NaHCO₃ (10 mL). The aqueous phase wasextracted with EtOAc (10 mL). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo to give Part E compound (488 mg; 80%).¹H NMR (400 MHz, CDCl₃) δ 6.17 (1H, d, J=3.95 Hz), 5.85 (2H, br. s.),3.92-4.05 (4H, m), 3.08 (2H, d, J=21.09 Hz), 1.18 (6 H, t, J=7.03 Hz).

Oxalyl chloride (2.0 M in DCM) (0.63 mL; 1.26 mmol) was added to a 0° C.mixture of Example 1 Part D compound (250 mg; 0.844 mmol) in DCM (2.5mL). DMF (10 uL) was added. Gas evolution occurred. After 1.5 h at RTthe reaction mixture was concentrated in vacuo. The residue was strippedfrom CHCl₃ (2×3 mL). The crude acid chloride was dissolved in DCM (3.0mL). Part E compound (253 mg; 1.013 mmol) was added followed by pyridine(205 uL; 2.532 mmol). After 2 h at RT the reaction was concentrated invacuo. The residue was partitioned between EtOAc (15 mL) and 0.5 Naqueous HCl (10 mL). The organic phase was washed with 0.5 N aqueous HCl(10 mL) and brine (10 mL). The solution was dried (MgSO₄), andconcentrated in vacuo. The crude product was chromatographed (SiO₂;continuous gradient from 0 to 100% solvent B over 3 min, hold at 100%solvent B for 14 min, where solvent A=hexanes and solvent B=EtOAc) togive the title compound (0.40 g; 89%) as an amorphous solid.[M+H]⁺=529.2; ¹H NMR (400 MHz, CD₃OD): δ 1.18 (m, 2H), 1.26 (t, 6H),1.51 (m, 2H), 1.64 (m, 3H), 1.83 (m, 3H), 2.22 (m, 1H), 3.09 (s, 3H),3.31 (d, 2H), 3.95 (t, 1H), 4.07 (m, 4H), 6.89 (d, J=4.03 Hz, 1H), 7.67(d, 2H), 7.92 (d, 2H).

Example 14

1 N aqueous NaOH (136 uL; 0.136 mmol) was added to a solution of Example13 Part F compound (50.5 mg; 0.096 mmol) in EtOH (100 μL). The reactionmixture was heated at 80° C. for 48 h, then was cooled to RT andconcentrated in vacuo. The crude product was purified by preparativeHPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flow rate=40 mL/min,10 to 100% solvent B over 16 min, hold to 20 min, where solventA=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to givethe title compound (12.5 mg; 26%) as an amorphous solid. [M+H]⁺=501.1;¹H NMR (400 MHz, CDCl₃): δ 1.13 (m, 2H), 1.30 (t, 3H), 1.48 (m, 2H),1.60 (m, 3H), 1.78 (m, 2H), 1.90 (m, 1H), 2.23 (m, 1H), 3.04 (s, 3H),3.28 (d, 2H), 4.05 (m, 3H), 6.68 (d, 1H), 7.68 (d, 2H), 7.88 (d, 2H).

Example 15

A solution of di-tert-butyl dicarbonate (1.66 g; 7.59 mmol) in THF (10mL) was added to a 0° C. solution of methyl2-aminothiazole-5-carboxylate (1.20 g; 7.59 mmol) in THF (20 mL). TEA(1.11 mL; 7.97 mmol) was added followed by a catalytic amount of 4-DMAP(10 mg). The reaction mixture was then stirred at RT for 20 h, then wasconcentrated in vacuo. The residue was partitioned between EtOAc (80 mL)and 0.2 N aqueous HCl (40 mL). The organic phase was washed with brine(40 mL), dried (MgSO₄) and concentrated in vacuo to give Part A compound(1.70 g; yield given below in Part B). The crude product was takenforward without further purification.

A solution of LiAlH₄ (7.60 mL of a 1.0 M solution in THF); 7.60 mmol)was added to a 0° C. solution of Part A compound (1.70 g; 6.58 mmol) inTHF (30 mL). The reaction mixture was stirred at RT for 1 h, then wascooled to 0° C. and carefully quenched by dropwise addition of H₂O (0.76mL). After 10 min, 5 N aqueous NaOH (0.38 mL) was added. After another10 min, the solution was filtered through a pad of Celite and thefiltrate was concentrated in vacuo. The crude product waschromatographed (SiO₂; continuous gradient from 0 to 100% solvent B over13 min, hold at 100% solvent B for 6 min, where solvent A=hexanes andsolvent B=EtOAc) to give Part B compound (0.80 g; 46%—two steps).

Part 1: Thionyl chloride (253 μL; 3.47 mmol) was added to a 0° C.mixture of Part B compound (200 mg; 0.869 mmol) in DCM (0.40 mL). Thereaction mixture was stirred at 0° C. for 2 h then was concentratedvacuo to give the crude chloride.

Part 2: The crude chloride was dissolved in THF (3.0 mL). (EtO)₃P (1.20mL; 6.95 mmol) was added. The reaction mixture was heated at 80° C. for16 h, then was cooled to RT and concentrated in vacuo. The crude productwas chromatographed (SiO₂; continuous gradient from 0 to 100% solvent Bover 8 min, switch to solvent C, hold at 100% solvent C for 7 min, wheresolvent A=hexanes, solvent B=EtOAc and solvent C=3% MeOH in EtOAc) togive Part C compound (270 mg; 89%—two steps).

TFA (0.80 mL) was added to a 0° C. solution of Part C compound (0.31 g;0.885 mmol) in DCM (2.4 mL). The reaction mixture was stirred at RT for3 h then was concentrated in vacuo. The residue was partitioned betweenCHCl₃ (10 mL) and sat. aqueous NaHCO₃ (10 mL). The aqueous phase wasextracted with CHCl₃ (10 mL). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo to give Part D compound (198 mg; 89%).

Oxalyl chloride (2.0 M in DCM) (101 uL; 0.202 mmol) was added to a 0° C.mixture of Example 1 Part D compound (40 mg; 0.135 mmol) in DCM (0.35mL). DMF (6 uL) was added. Gas evolution occurred. The reaction mixturewas then stirred at RT for 1.5 h then was concentrated in vacuo. Theresidue was stripped from CHCl₃ (2×1 mL). The crude acid chloride wasdissolved in DCM (0.45 mL). Part D compound (47.3 mg; 0.189 mmol) wasadded followed by pyridine (33.0 uL; 0.405 mmol). After 4 h at RT thereaction was concentrated in vacuo. The residue was partitioned betweenEtOAc (6 mL) and brine (4 mL). The organic phase was dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by preparativeHPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flow rate=40 mL/min,15 to 100% solvent B over 10 min, hold to 15 min, where solventA=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to givethe title compound (46 mg; 65%) as a white solid. [M+H]⁺=529.1; ¹H NMR(400 MHz, CD₃OD): δ 1.18 (m, 2H), 1.29 (t, 6H), 1.49 (m, 2H), 1.63 (m,3H), 1.80 (m, 3H), 2.22 (m, 1H), 3.09 (s, 3H), 3.43 (d, 2H), 3.96 (t,1H), 4.09 (m, 4H), 7.26 (d, J=4.4 Hz, 1H), 7.67 (d, 2H), 7.92 (d, 2H).

Example 16

Oxalyl chloride (169 μL of a 2 M solution in DCM; 0.338 mmol) was addedto a mixture of Example 1 Part D compound (50 mg; 0.169 mmol) in DCM(0.35 mL). The solution was cooled to 0° C. DMF (5 uL) was added. Gasevolution occurred. After 2 h at RT the reaction mixture wasconcentrated in vacuo. The residue was stripped from CHCl₃ (2×1 mL). Thecrude acid chloride was dissolved in DCM (0.5 mL).5-bromo-2-pyrazinamine (44 mg; 0.253 mmol) was added followed bypyridine (20.5 uL; 0.253 mmol). The reaction mixture was stirred at RTfor 3 h, then was concentrated in vacuo. The residue was partitionedbetween EtOAc (6 mL) and brine (4 mL). The organic phase was dried(MgSO₄) and concentrated in vacuo. The crude product was chromatographed(SiO₂; continuous gradient from 0 to 30% solvent B over 30 min, then 30%to 65% solvent B over 5 min, then hold at 65% solvent B for 5 min, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (64 mg;84%).

A solution of Part A compound (44 mg; 0.097 mmol) in THF (degassed)(0.50 mL) was added to a reaction flask containing (Ph₃P)₄Pd(0)(22.4 mg;0.019 mmol). (MeO)₃P (11.6 μL; 0.126 mmol) was added followed by TEA(21.6 μL; 0.155 mmol). The reaction vessel was capped and the reactionmixture was heated at 75° C. for 6 h, then was cooled to RT andconcentrated in vacuo. The crude product was purified by preparativeHPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flow rate=40 mL/min,15 to 100% solvent B over 10 min, hold to 13 min, where solventA=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to givePart B compound (17 mg; 38%).

TMSCHN₂ (2.0 M in hexane) (73 μL; 0.145 mmol) was added to a mixture ofPart B compound (17 mg; 0.036 mmol) in Et₂O (75 μL) and THF (250 μL).After stirring at RT for 1 h the reaction mixture was concentrated invacuo. The crude product was purified by preparative HPLC(YMC reversephase ODS-A-5 u 20×100 mm column; flow rate=20 mL/min., 20 to 100%solvent B over 10 min, hold to 15 min, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to give the titlecompound (9 mg; 51%) as a colorless solid. [M+H]⁺=482.2; ¹H NMR (400MHz, CD₃OD): δ 1.19 (m, 2H), 1.51 (m, 2H), 1.64 (m, 3H), 1.83 (m, 3H),2.22 (m, 1H), 3.09 (s, 3H), 3.83 (d, 3H), 3.86 (d, 3H), 4.04 (t, 1H),7.70 (d, 2H), 7.92 (d, 2H), 8.71 (s, 1H), 9.59 (s, 1H).

Example 17

TEA (311 uL; 2.23 mmol) was added to a mixture of 4-bromo-picolinic acid(450 mg; 2.23 mmol) in toluene (6.7 mL). Diphenylphosphoryl azide (480uL; 2.23 mmol) was added and the reaction was stirred for 30 min at RT,after which tert-butanol (427 uL; 4.46 mmol) was added. The reactionmixture was heated at 90° C. for 2 h, then was cooled to RT. Thesolution was diluted with EtOAc (15 mL), washed with 10% aqueous Na₂CO₃(3×3 mL) and brine (10 mL), dried (MgSO₄) and concentrated in vacuo. Thecrude product was chromatographed (SiO₂; continuous gradient from 0 to75% solvent B over 15 min, where solvent A=hexanes and solvent B=EtOAc)to give Part A compound (0.39 g; 65%).

HCl (1 mL of a 4.0 M solution in 1,4 dioxane) was added to a reactionvessel containing Part A compound (106.5 mg; 0.390 mmol). After stirringat RT for 20 h the reaction mixture was concentrated in vacuo. The crudeproduct was stirred with hexanes (3 mL). The HCl salt of Part B compound(81 mg; 100%) was isolated by filtration.

Oxalyl chloride (152 μL of a 2 M solution in DCM; 0.304 mmol) was addedto a mixture of Example 1 Part D compound (60 mg; 0.202 mmol) in DCM(0.4 mL). The solution was cooled to 0° C. DMF (7 μL) was added. Gasevolution occurred. After 2 h at RT the reaction mixture wasconcentrated in vacuo. The residue was stripped from CHCl₃ (2×1 mL). Thecrude acid chloride was then dissolved in DCM (0.5 mL). Part B compound(53 mg; 0.253 mmol) was added followed by pyridine (49 uL; 0.606 mmol).The reaction mixture was stirred at RT for 2 h then was concentrated invacuo. The residue was partitioned between EtOAc (8 mL) and brine (4mL). The organic phase was dried (MgSO₄) and concentrated in vacuo. Thecrude product was chromatographed (SiO₂; continuous gradient from 0 to100% solvent B over 10 min, where solvent A=hexanes and solvent B=EtOAc)to give Part C compound (72 mg; 79%).

A solution of Part C compound (66 mg; 0.146 mmol) in THF (degassed)(0.38 mL) was added to a reaction flask containing (Ph₃P)₄Pd(0)(34 mg;0.029 mmol). H(O)P(OEt)₂ (21 μL; 0.161 mmol) was added followed by TEA(24.4 μL; 0.175 mmol). The reaction vessel was capped and the reactionmixture was heated at 75° C. for 16 h, then was cooled to RT andconcentrated in vacuo. The crude product was purified by preparativeHPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flow rate=40 mL/min,35 to 100% solvent B over 12 min, hold to 14 min, where solventA=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to givethe title compound (49 mg; 66%) as a white solid. [M+H]⁺=509.1; ¹H NMR(400 MHz, CD₃OD): δ 1.19 (m, 2H), 1.34 (m, 6H), 1.52 (m, 2H), 1.65 (m,3H), 1.84 (m, 3H), 2.23 (m, 1H), 3.09 (s, 3H), 4.01 (t, 1H), 4.16 (m,4H), 7.38 (dd, 1H), 7.71 (d, 2H), 7.92 (d, 2H), 8.47 (m, 2H).

Example 18

A solution of di-tert-butyl dicarbonate (1.03 g; 4.73 mmol) in toluene(15 mL) was added to a reaction vessel containing (ethyl2-(2-aminothiazol-4-yl)acetate (0.80 g; 4.30 mmol). The reaction mixturewas heated at 85° C. for 24 h, then was cooled to RT and concentrated invacuo to give Part A compound (1.14 g; quant. yield). The crude compoundwas carried forward without further purification.

A solution of LiAlH₄ (4.30 mL of a 1 M solution in THF; 4.40 mmol) wasadded to a 0° C. solution of crude Part A compound (1.14 g; 3.98 mmol)in THF (13 mL). The reaction mixture was stirred at 0° C. for 2 h, thenwas carefully quenched by dropwise addition of sat. aqueous NH₄Cl (0.6mL). The solution was partitioned between EtOAc (20 mL) and brine (10mL). The organic phase was washed with brine (10 mL), dried (MgSO₄) andconcentrated in vacuo. The crude product was chromatographed (SiO₂;continuous gradient from 0 to 100% solvent B over 8 min, hold at 100%solvent B for 8 min, where solvent A=hexanes and solvent B=EtOAc) togive Part B compound (0.42 g; 43%).

A solution of CH₃SO₂Cl (140 μL; 1.81 mmol) in DCM (1.7 mL) was added toa 0° C. solution of Part B compound (0.42 g; 1.72 mmol) and TEA (264 uL;1.89 mmol) in DCM (4.0 mL). After 30 min at 0° C. the reaction mixturewas diluted with acetone (5.7 mL). LiBr (896 mg; 10.32 mmol) was added.The reaction was stirred at RT for 1 h, then was partitioned betweenEt₂O (10 mL) and sat. aqueous NH₄Cl (10 mL). The organic phase waswashed with sat. aqueous NH₄Cl (10 mL) and brine (10 mL), dried (MgSO₄)and concentrated in vacuo to give Part C compound (0.50 g; 94%).

Part 1: Part C compound (0.50 g; 1.63 mmol) was dissolved in neat(EtO)₃P (1.0 mL). The reaction mixture was heated at 130° C. for 2 h; atthis point analytical HPLC showed multiple peaks. The reaction wascooled to RT and concentrated in vacuo. The crude product waschromatographed (SiO₂; continuous gradient from 0 to 100% solvent B over7 min, switch to solvent C, hold at 100% solvent C for 7 min, wheresolvent A=hexanes, solvent B=EtOAc and solvent C=3% MeOH in EtOAc). Thecompound was not pure at this point (65% purity).

Part 2: To a 0° C. solution of the impure intermediate from Part 1 inDCM (0.8 mL) was added TFA (0.4 mL). The reaction was allowed to warm toRT and stirred at RT for 2 h, then was concentrated in vacuo. Theresidue was partitioned between EtOAc (10 mL) and sat. aqueous NaHCO₃(10 mL). The organic phase was dried (MgSO₄) and concentrated in vacuoto give Part D compound (73 mg; 17%-two steps). (65% purity).

Oxalyl chloride (2.0 M in DCM) (78 μL; 0.155 mmol) was added to amixture of Example 1 Part D compound (33 mg; 0.111 mmol) in DCM (0.25mL). The solution was cooled to 0° C. DMF (7 μL) was added. Gasevolution occurred. After 1.5 h at RT the reaction mixture wasconcentrated in vacuo. The residue was stripped from CHCl₃ (2×0.8 mL).The crude acid chloride was dissolved in DCM (0.25 mL). Part D compound(38 mg; 0.144 mmol) was added followed by pyridine (27 uL; 0.333 mmol).The reaction mixture was stirred at RT for 2 h, then was concentrated invacuo. The residue was partitioned between EtOAc (8 mL) and 0.5 Naqueous HCl (4 mL). The organic phase was washed with brine (4 mL),dried (MgSO₄), and concentrated in vacuo. The crude product was purifiedby preparative HPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flowrate=40 mL/min, 20 to 100% solvent B over 10 min, hold to 14 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to give title compound (29 mg; 48%) as an amorphous solid. [M+H]⁺=543.0;¹H NMR (400 MHz, CD₃OD): δ 1.19 (m, 2H), 1.27 (t, 6H), 1.50 (m, 2H),1.63 (m, 3H), 1.81 (m, 3H), 2.20 (m, 3H), 2.87 (m, 2H), 3.09 (s, 3H),3.95 (t, 1H), 4.06 (m, 4H), 6.77 (s, 1H), 7.67 (d, 2H), 7.92 (d, 2H).

Example 19

DMF (20 mL) was added to a reaction flask containing5-bromo-2-pyrazinamine (1.00 g; 5.75 mmol), (Ph₃P)₄Pd(0) (199 mg; 0.173mmol) and LiCl (853 mg; 20.13 mmol). DIPEA (2.50 mL; 14.38 mmol) wasadded followed by tributyl (vinyl)tin (2.52 mL; 8.62 mmol). The reactionmixture was heated at 120° C. for 4 h, then was cooled to RT. A solutionof aqueous sat. KF (20 mL) was added. After stirring for 16 h themixture was diluted with EtOAc (80 mL) and filtered through Celite. Thefiltrate was washed with H₂O (80 mL), dried (MgSO₄) and concentrated invacuo. The crude product was chromatographed (SiO₂; continuous gradientfrom 0 to 100% solvent B over 13 min, hold at 100% for 4 min, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.41 g;59%).

Oxalyl chloride (127 μL of a 2 M solution in DCM; 0.253 mmol) was addedto a mixture of Example 1 Part D compound (50 mg; 0.169 mmol) in DCM(0.5 mL). The solution was cooled to 0° C. DMF (7 μL) was added. Gasevolution occurred. After 1.5 h at RT the reaction mixture wasconcentrated in vacuo. The residue was stripped from CHCl₃ (2×1 mL). Thecrude acid chloride was then dissolved in DCM (0.6 mL). Part A compound(24.5 mg; 0.202 mmol) was added followed by pyridine (41 uL; 0.507mmol). The reaction mixture was stirred at RT for 1.5 h, then wasconcentrated in vacuo. The crude product was chromatographed (SiO₂;continuous gradient from 0 to 100% solvent B over 12 min, hold at 100%solvent B for 3 min, where solvent A=hexanes and solvent B=EtOAc) togive Part B compound (70 mg; 100%).

Acetic acid (15 μL) was added to a solution of Part B compound (70 mg;0.175 mmol) in DCM (0.50 mL). The solution was cooled to −78° C. (dryice/acetone). Ozone was bubbled through the solution until it turnedlight blue (˜4 min) The dry ice/acetone bath was removed and thereaction was allowed to warm to RT. After 5 min of stirring at RT thesolution was diluted with DCM (3 mL). Sat. aqueous NaHCO₃ (3 mL) wasadded (emulsion formed). The mixture was concentrated in vacuo to removeDCM. The aqueous solution was then extracted with EtOAc (4 mL). Theorganic phase was dried (MgSO₄) and concentrated in vacuo to give Part Ccompound (55 mg; 78%).

Diethyl phosphite (8.0 μL; 0.062 mmol) was added to a solution of Part Ccompound (25 mg; 0.062 mmol) in THF (0.30 mL). TEA (8.68 uL; 0.062 mmol)was then added. After 8 h at RT the solution was concentrated in vacuo.The crude product was purified by preparative HPLC(YMC reverse phaseODS-A-5 u 30×100 mm column; flow rate=40 mL/min, 15 to 100% solvent Bover 15 min, hold to 20 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA andsolvent B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (15 mg;45%; amorphous solid) as a 1:1 mixture of diastereomers. [M+H]⁺=540.2;¹H NMR (400 MHz, CDCl₃): δ 1.15 (m, 2H), 1.31 (m, 6H), 1.48 (m, 2H),1.62 (m, 3H), 1.78 (m, 2H), 1.93 (m, 1H), 2.22 (m, 1H), 3.88 (m, 1H),4.20 (m, 4H), 5.13 (dd, 1H), 7.63 (d, 2H), 7.89 (d, 2H), 8.34 (d, 1H),9.11 (d, 1H), 9.43 (s, 1H).

Example 20

A solution of Example 19 Part C compound (26 mg; 0.065 mmol) in DCM (150uL) was added to a solution of CH₂(PO₃Et₂)₂ (16.2 μL; 0.065 mmol) in 5 Naqueous NaOH (150 μL). After 1 h at RT the reaction mixture waspartitioned between DCM (3 mL) and H₂O (2 mL). The organic phase wasdried (MgSO₄) and concentrated in vacuo to give Part A compound (35 mg;100%).

10% Pd/C (3 mg) was added to a solution of Part A compound (35 mg; 0.065mmol) in MeOH (0.30 mL). A H₂ atmosphere was introduced via balloon.After 6 h the reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The crude product was purified by preparativeHPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flow rate=40 mL/min,20 to 100% solvent B over 11 min, hold to 15 min, where solventA=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to givetitle compound (11 mg; 31%) as an amorphous solid. [M+H]⁺=538.2; ¹H NMR(400 MHz, CDCl₃): δ 1.15 (m, 2H), 1.30 (m, 8H), 1.48 (m, 2H), 1.61 (m,3H), 1.76 (m, 2H), 1.93 (m, 1H), 2.22 (m, 3H), 3.05 (s, 3H), 3.74 (m,1H), 4.09 (m, 4H), 7.61 (d, 2H), 7.92 (d, 2H), 8.08 (s, 1H), 8.29 (s,1H), 9.44 (s, 1H).

Example 21

Oxalyl chloride (203 μL of a 2 M solution in DCM; 0.406 mmol) was addedto a 0° C. mixture of Example 1 Part D compound (80 mg; 0.270 mmol) inDCM (0.70 mL). DMF (10 uL) was added. Gas evolution occurred. Thereaction mixture was stirred at RT for 1.5 h, then was concentrated invacuo. The residue was stripped from CHCl₃ (2×2 mL). The crude acidchloride was dissolved in DCM (0.90 mL). 2-amino-5-formylthiazole (45.0mg; 0.351 mmol) was added followed by pyridine (66.0 uL; 0.810 mmol).After 16 h at RT the reaction was concentrated in vacuo. The crudeproduct was chromatographed (SiO₂; continuous gradient from 0 to 100%solvent B over 6 min, hold at 100% solvent B for 8 min, where solventA=hexanes and solvent B=EtOAc) to give Part A compound (27 mg; 25%).

H(O)P(OEt)₂ (8.9 μL; 0.069 mmol) was added to a solution of Part Acompound (27 mg; 0.066 mmol) in THF (0.30 mL). TEA (9.6 μL; 0.069 mmol)was added. The reaction mixture was stirred at RT for 20 h, after whichmore H(O)P(OEt)₂ (8.89 uL; 0.069 mmol) and TEA (9.62 uL; 0.069 mmol)were added along with THF (0.10 mL). After 20 h the reaction was heatedat 45° C. for 16 h, then was cooled to RT. After two weeks at RT theresidue which had formed was purified by preparative HPLC(YMC reversephase ODS-A-5 u 30×100 mm column; flow rate=40 mL/min, 15 to 100%solvent B over 20 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA andsolvent B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (27 mg;75%; amorphous solid) as a 1:1 mixture of diastereomers. [M+H]⁺=540.2;¹H NMR (400 MHz, CDCl₃): δ 1.16 (m, 2H), 1.32 (m, 6H), 1.49 (m, 2H),1.62 (m, 3H), 1.78 (m, 2H), 1.95 (m, 1H), 2.24 (m, 1H), 3.04 (s, 3H),4.01 (t, 1H), 4.21 (m, 4H), 5.18 (d, 1H), 7.37 (s, 1H), 7.65 (d, 2H),7.91 (d, 2H).

Example 22

To a solution of 2-amino-5-bromothiazole hydrobromide (10.0 g, 38.4mmol) in MeOH (50 mL) was added KSCN (15.0 g, 160 mmol). The reactionmixture was stirred at RT for 18 h, then was concentrated in vacuo, andH₂O (40 mL) was added to the residue. The mixture was adjusted to pH 12with 1N aqueous NaOH. A precipitate was formed, which was collected bysuction filtration, and washed with H₂O (3×) and Et₂O (3×). The solidwas dried in vacuo for 18 h to give Part A compound as a brown solid(2.8 g, 47%).

To a solution of Part A thiocyanate (800 mg, 5.09 mmol) and Example 1D(1.51 g, 5.09 mmol) in THF (20 mL) was added DEPBT (3.05 g, 10.18 mmol)and iPr₂NEt (1.8 mL, 10.18 mmol). The reaction mixture was stirred at RTfor 18 h, then was concentrated in vacuo. The residue was taken up inEtOAc and brine, and extracted with EtOAc (3×). The combined organicextracts were washed with 1N aqueous HCl, H₂O, 5% aqueous NaHCO₃, H₂O,and brine, dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient 10% EtOAc/Hex to 100%EtOAc/Hexane) to give Part B compound (927 mg, 42%) as an orange solid.

To a 0° C. solution of thiocyanate B (50 mg, 0.11 mmol) in absolute EtOH(2 mL) was added NaBH₄ (7 mg, 0.22 mmol). The mixture was stirred at 0°C. for 1 h, after which excess NaBH₄ was cautiously quenched withacetone (0.5 mL). The mixture was warmed to RT, and was added to a flaskcharged with ICH₂PO₃Et₂ (41 mg, 0.15 mmol). The reaction was stirred atRT for 18 h, then was concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex Luna 5 u C18 21.2×100 mm column; detectionat 220 nm; flow rate=20 mL/min; continuous gradient from 70% A to 100% Bover 8 min+7 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to provide the title compound (25.1 mg, 39%yield) as an off white lyophilate. [M+H]⁺=561.1; ¹H NMR (400 MHz,DMSO-D6): δ 7.83 (d, J=8.4, 2H), 7.58 (d, J=8.3, 2H), 7.51 (s, 1H), 3.92(m, 5H), 3.15 (s, 2H), 3.12 (s, 3H), 2.09-1.36 (m, 11H), 1.12 (m, 6H).

Example 23

To a solution of Example 22 compound (20 mg, 0.04 mmol) in MeOH (1 mL)and THF (1 mL) was added p-toluenesulfonyl imidazole (24 mg, 0.11 mmol),30% aqueous H₂O₂ (0.02 mL, 0.14 mmol), and 1N aqueous NaOH (1.0 mL). Thereaction was stirred at RT for 3 h, then was concentrated in vacuo. Theresidue was purified by preparative HPLC (Phenomenex Luna 5 u C1821.2×100 mm column; detection at 220 nm; flow rate=20 mL/min; continuousgradient from 70% A to 100% B over 8 min+7 min hold time at 100% B,where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to providethe title compound (12 mg, 57% yield) as a white lyophilate.[M+H]⁺=593.2; ¹H NMR (400 MHz, DMSO-D6): δ 8.00 (s, 1H), 7.84 (d, J=8.4,2H), 7.59 (d, J=8.4, 2H), 4.08-3.94 (m, 5H), 3.13 (s, 2H), 3.10 (s, 3H),2.02-1.10 (m, 11H), 1.10-1.06 (m, 6H).

Example 24

To a solution of 3,5-dimethylbenzoic acid (800 mg, 5.3 mmol) in CH₂Cl₂(20 mL) was added oxalyl chloride (0.51 mL, 5.8 mmol) and DMF (0.1 mL).The reaction mixture was stirred at RT for 2 h, then was concentrated invacuo. The residue was taken up in THF (20 mL), and Example 22 Part Aamine (922 mg, 5.8 mmol) and pyridine (0.86 mL, 10.6 mmol) were added.The mixture was stirred at RT for 18 h, then was diluted with EtOAc (60mL), washed with H₂O and brine, and extracted with EtOAc (2×). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (10% EtOAc/Hex to 100% EtOAc/Hexane) togive Part A compound (770 mg, 51% yield) as a brown solid.

To a 0° C. solution of Part A compound (50 mg, 0.17 mmol) in absoluteEtOH (2 mL) was added NaBH₄ (13 mg, 0.35 mmol), and the mixture wasstirred for 1 h at 0° C. The excess NaBH₄ was quenched with acetone (0.5mL), and the mixture was warmed to RT. The mixture was added to a flaskcharged with ICH₂PO₃Et₂ (62 mg, 0.22 mmol). The reaction was stirred atRT for 18 h, then was concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex Luna 5 μm C18 21.2×100 mm column; detectionat 220 nm; flow rate=20 mL/min; continuous gradient from 70% A to 100% Bover 8 min+7 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to provide the title compound (22.4 mg, 32%yield) as a white solid. [M+H]⁺=415.1; ¹H NMR (400 MHz, DMSO-D6): δ 7.71(s, 1H), 7.66 (s, 2H), 7.27 (s, 1H), 4.02 (m, 4H), 3.27 (s, 2H), 2.34(s, 6H), 1.21 (m, 6H).

Example 25

A mixture of tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (399 mg,1.23 mmol) and (iPrO)₃P (2 mL) was heated at 100° C. overnight. Thereaction mixture was cooled to RT, then was chromatographed (120 g SiO₂;continuous gradient from 0-50% EtOAc in DCM, followed by a continuousgradient from 0-10% MeOH in DCM) to give 399 mg (86% yield) of Part Acompound as a light yellow solid (88% purity by HPLC). [M+H]⁺=374.3;¹H-NMR (400 MHz, CDCl₃): δ 9.18 (s, 1H), 8.24 (s, 1H), 7.32 (s, 1H),4.67 (m, 2H), 3.33 (d, 2H), 1.54 (s, 9H), 1.25-1.30 (m, 12H).

A 0° C. solution of Part A compound (200 mg, 0.535 mmol) in DCM (1 mL)was treated with 1 mL of 4N aqueous HCl in dioxane under Ar. Thereaction mixture was allowed to warm to RT overnight, then wasconcentrated in vacuo. The residue was dissolved in water (5 mL) andextracted with Et₂O to remove an impurity. The aqueous solution wasbasified with 1 N aqueous NaOH and extracted with DCM (3×2 mL). Thecombined organic extracts were rinsed with brine, dried (MgSO₄), andconcentrated in vacuo to provide 103 mg (71% yield) of diisopropyl(5-aminopyrazin-2-yl)methylphosphonate as a yellow, waxy solid.[M+H]⁺=274.3. This material was used directly in the next step withoutfurther purification.

Example 1D acid was converted to the corresponding acid chloride usingoxalyl chloride (as described in Example 2 Part A). The acid chloridewas transferred with two 0.3 mL portions of DCM into a 0° C. mixture ofthe above amine (45 mg, 0.165 mmol) and pyridine (53.4 μL, 0.66 mmol) inDCM (0.7 mL) under Ar. The reaction was allowed to warm to RT overnight,then was extracted with DCM (5 mL). The organic extract was washed with2 mL each of 0.1N aqueous HCl, water, and brine, was dried (MgSO₄), andconcentrated in vacuo to afford 142 mg of crude product. The crudematerial was chromatographed (40 g SiO₂; continuous gradient from10-100% EtOAc in DCM) to give the title compound (25.6 mg, 28% yield) asa colorless oil. [M+H]⁺=552.4; ¹H-NMR (400 MHz, CDCl₃): δ 9.40 (s, 1H),8.24 (s, 2H), 7.93 (d, 2H), 7.61 (d, 2H), 4.68 (m, 2H), 3.74 (m, 1H),3.34 (d, 2H), 3.05 (s, 3H), 2.22 (m, 1H), 1.95 (m, 1H), 1.10-2.83 (m,9H), 1.25-1.29 (m, 12H).

Example 26

To a rapidly stirred mixture of methyl 3,5-dihydroxybenzoate (38 g,0.226 mol) and K₂CO₃ (47.7 g, 0.345 mol) in DMF (150 mL) heated at 120°C. under Ar was added a solution of 1-fluoro-4-(methylsulfonyl)benzene(20 g, 0.115 mol) in DMF (50 mL) over 3 h. After heating at 120° C.overnight, the reaction mixture was cooled to RT, diluted with DMF (300mL), and then treated with Celite® as a filter aid. The heterogeneousreaction mixture was filtered, and the filter cake was thoroughly rinsedwith more DMF. The combined filtrates were concentrated in vacuo, andthe residue was partitioned between 1N aqueous HCl (200 mL) and EtOAc(250 mL). A further 100 mL of water was added. The aqueous layer wasextracted with EtOAc (200 mL), and the combined organic extracts wererinsed with water and brine (250 mL each), and dried (MgSO₄). Volatileswere removed in vacuo. The residue was chromatogaphed in 3 portions.Each portion was absorbed onto SiO₂ (˜20 g) and chromatographed (330 gSiO₂; elution with a continuous gradient of 0-20% EtOAc in CH₂Cl₂followed by isocratic 20% EtOAc: CH₂Cl₂) to give Part A compound (14.77g; combined yield of 40%) as a white solid. [M+H]⁺=323.0; ¹H-NMR (400MHz, CDCl₃): δ 7.89 (d, 2H), 7.33 (s, 1H), 7.22 (s, 1H), 7.11 (dd, 2H),6.89 (d, 1H), 3.89 (s, 3H), 3.07 (s, 3H).

To a 5° C. mixture of Part A compound (5 g, 15.5 mmol),(R)-(−)-1-methoxy-2-propanol (2 mL, 20.4 mmol) and polymer-supportedPh₃P (13.4 g of 3 mmol/g, 40.2 mmol) in THF (175 mL) was added dropwisea solution of DIAD (4.5 mL, 23.2 mmol) in THF (25 mL) over 25 min underAr (internal temperature maintained at 5° C.). The reaction mixture wasallowed to warm to RT overnight, and was then filtered. The solids werethoroughly washed with THF and CH₂Cl₂. The combined filtrates wereconcentrated in vacuo, re-dissolved in CH₂Cl₂ and divided in 2 equalportions. The first portion was chromatographed (330 g SiO₂; elutionwith a continuous gradient of 0-10% EtOAc in CH₂Cl₂ over 40 min) to give2.53 g of pure Part B compound as a colorless oil. Impure productfractions from this column were combined with the rest of the crudeproduct and this mixture was chromatographed as above on 330 g SiO₂, butwith a continuous gradient from 0-8% EtOAc in CH₂Cl₂ to give Part Bcompound (3.02 g) as a colorless oil. The combined yield of Part Bcompound was 5.55 g (90%). [M+H]⁺=395.0; ¹H-NMR (400 MHz, CDCl₃): δ 7.90(d, 2H), 7.48 (s, 1H), 7.30 (s, 1H), 7.11 (dd, 2H), 6.86 (d, 1H), 4.61(m, 1H), 3.90 (s, 3H), 3.49-3.62 (m, 2H), 3.40 (s, 3H), 3.07 (s, 3H),1.32 (d, 3H).

To a 0° C. solution of Part B compound (4.24 g, 10.75 mmol) in THF (50mL) and water (15 mL) was added LiOH.H₂O (1.287 g, 53.7 mmol). Thereaction mixture was allowed to warm to RT overnight (reaction completeby LC/MS). The reaction mixture was concentrated in vacuo and 50 mL ofH₂O was added; the solution was acidified with 5N aqueous HCl. Themixture was extracted with EtOAc (2×100 mL). The combined EtOAc extractswere washed with brine (50 mL), dried (MgSO₄) and concentrated in vacuoto provide Part C compound (3.95 g, 96.5% yield) as a colorless glass.[M+H]⁺=381.1; ¹H-NMR (400 MHz, CDCl₃): δ 7.91 (d, 2H), 7.52 (s, 1H),7.35 (s, 1H), 7.13 (dd, 2H), 6.90 (s, 1H), 4.61 (m, 1H), 3.52-3.64 (m,2H), 3.42 (s, 3H), 3.07 (s, 3H), 1.33 (d, 3H).

To a 0° C. solution of Example 25A compound (199 mg, 0.533 mmol) in DCM(1 mL) was added TFA (1 mL) under Ar. The reaction mixture was allowedto warm to RT. After 5.5 h, the reaction mixture was concentrated invacuo and partitioned between 0.5N aqueous HCl and Et₂O (4 mL each). Theaqueous layer was basified with solid K₂CO₃, then extracted with DCM(3×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to provide 108 mg (74%) ofdiisopropyl (5-aminopyrazin-2-yl)methylphosphonate isolated as a yellowsolid. [M+H]⁺=274.3.

The Part C acid (32 mg, 0.0841 mmol) was converted to the correspondingacid chloride using oxalyl chloride (as described in Example 2 Part A).The crude acid chloride was transferred with two portions (0.2 mL each)of DCM to a mixture of diisopropyl(5-aminopyrazin-2-yl)methylphosphonate (25.3 mg, 0.0926 mmol) andpyridine (27.2 μL, 0.370 mmol) in DCM (0.4 mL) cooled to 0° C. under Ar.The reaction was allowed to warm to RT overnight. The reaction mixturewas then extracted with DCM (4 mL), washed with 2 mL each of 0.5Naqueous HCl, water, sat. aqueous NaHCO₃ and brine, dried (MgSO₄) andconcentrated in vacuo. The crude product (47 mg) was chromatographed (12g SiO₂; elution with a continuous gradient from 15 to 100% EtOAc in DCM)to provide 17.6 mg (30%) of the title compound as a colorless oil.[M+H]⁺=636.3; ¹H-NMR (400 MHz, CDCl₃): δ 9.57 (s, 1H), 8.46 (s, 1H),8.34 (s, 1H), 7.93 (d, 2H), 7.36 (s, 1H), 7.18 (s, 1H), 7.17 (d, 2H),6.87 (s, 1H), 4.60-4.75 (m, 3H), 3.52-3.63 (m, 2H), 3.41 (s, 3H), 3.39(d, 2H), 3.08 (s, 3H), 1.25-1.36 (m, 15H).

Example 27 (Isomer A) and Example 28 (Isomer B)

A mixture of tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (300 mg,1.04 mmol) and diethyl methylphosphonite (0.2 mL) in THF (0.2 mL) washeated overnight at 100° C., then cooled to RT and dissolved in EtOAc(15 mL). The solution was washed with water (3×5 mL) and brine (5 mL),was dried (MgSO₄), and concentrated in vacuo. The crude product (279 mg)was chromatographed (SiO₂; 80 g; elution with a continuous gradient from0-100% EtOAc in DCM) to give Part A compound (114 mg) as a waxy whitesolid, which still contained some by-product from the diethylmethylphosphonite reagent. [M+H]⁺=316.3.

A 0° C. solution of Part A compound (114 mg, 0.361 mmol) in DCM (1 mL)was treated with 4N HCl in dioxane (1 mL). The reaction was allowed towarm to RT overnight, then was diluted with Et₂O to fully precipitatethe desired product HCl salt and decanted. This process was repeatedseveral times to yield Part B compound (82 mg; 90%) as a white solid.LC/MS showed the correct [M+H]⁺=216.3 for the free amine.

Example 1 Part D compound (91.9 mg, 0.310 mmol) was converted to thecorresponding acid chloride using oxalyl chloride (as described inExample 2 Part A). The crude acid chloride was dissolved in a minimalvolume of DCM and added to a 0° C. mixture of Part B compound (52 mg,0.242 mmol) and pyridine (78.2 μL, 0.968 mmol) in DCM (1 mL) under Ar.The reaction was allowed to warm to RT overnight, then was diluted withDCM (7 mL) and washed with two 2 mL portions of 0.5N aqueous HCl, water,sat. aqueous NaHCO₃ and brine, dried (MgSO₄) and concentrated in vacuo.The crude material (150 mg) was chromatographed (40 g SiO₂; elution witha continuous gradient from 0 to 100% EtOAc in DCM, followed by acontinuous gradient from 0-10% MeOH in DCM) to give the productdiastereomers (43 mg) as a mixture. Preparative reverse phase HPLC on aYMC ODS-A 5μ 30×100 mm column (elution with a continuous 40-100%gradient from 90:10:0.1 to 10:90:0.1, water:MeOH:TFA) gave 17.9 mg of afaster-eluting isomer A and 18.3 mg of the slower-eluting isomer B. Eachof the above samples was dissolved in 6 mL of DCM and rinsed with 2 mLof sat. aqueous NaHCO₃ to remove TFA. The DCM solutions were rinsed withbrine, dried (MgSO₄) and concentrated in vacuo to give the desiredIsomers A and B.

Isomer A (Example 27) was obtained as 16.8 mg of a colorless glass.[M+H]⁺=494.4; ¹H-NMR (400 MHz, CD₃OD): δ 9.31 (s, 1H), 8.31 (s, 1H),7.92 (m, 2H), 7.72 (m, 2H), 3.96-4.12 (m, 3H), 3.44 (d, 2H), 3.30 (s,3H), 2.18-2.26 (m, 1H), 1.13-1.89 (m, 9H), 1.56 (d, 3H), 1.27 (m, 3H).

Isomer B (Example 28) was obtained as 15.6 mg of a colorless glass:[M+H]⁺=494.4; ¹H-NMR (400 MHz, CD₃OD): δ 9.31 (s, 1H), 8.31 (s, 1H),7.91 (m, 2H), 7.70 (m, 2H), 3.97-4.12 (m, 3H), 3.44 (d, 2H), 3.30 (s,3H), 2.16-2.26 (m, 1H), 1.13-1.88 (m, 9H), 1.54 (d, 3H), 1.28 (m, 3H).

Example 29

EDC (19.7 mg, 0.100 mmol) was added to a 0° C. mixture of the Example26C acid (34.6 mg, 0.091 mmol), HOAT (14.8 mg, 0.109 mmol), diethyl(6-aminopyridin-3-yl)methylphosphonate (24.4 mg, 0.100 mmol) and Et₃N(12.6 μL, 0.091 mmol) in 0.7 mL of DCM under Ar. The reaction mixturewas allowed to warm to RT overnight. An additional 12 mg of amine wasadded and stirring was continued for 4 days. The reaction was extractedwith 3 mL of DCM and washed with 1 mL each of 0.5N aqueous HCl, water,sat. aqueous NaHCO₃ and brine, dried (MgSO₄) and concentrated in vacuo.The crude product (34 mg) was purified by preparative reverse phase HPLCon a 30×100 mm Phenomenex Axia Luna 5 μC18 column (continuous gradientfrom 30-100% 90:10:0.1 to 10:90:0.1, water:CH₃CN: TFA) to provide 29 mgof desired product. This material was dissolved in 3 mL of DCM andwashed with two 1 mL portions of sat. aqueous NaHCO₃, brine and dried(MgSO₄). Concentration in vacuo provided 20.8 mg (38% yield) of thetitle compound as a colorless oil. [M+H]⁺=607.3; ¹H-NMR (400 MHz,CDCl₃): δ 8.54 (s, 1H), 8.30 (d, 1H), 8.20 (s, 1H), 7.91 (d, 2H), 7.72(d, 1H), 7.34 (s, 1H), 7.12-7.17 (m, 3H), 6.85 (s, 1H), 4.62 (m, 1H),4.06 (m, 4H), 3.50-3.62 (m, 2H), 3.41 (s, 3H), 3.11 (d, 2H), 3.08 (s,3H), 1.23-1.35 (m, 9H).

Example 30

Imidazole (1.86 g, 27.4 mmol) was added to a mixture of(R)-propane-1,2-diol (1 mL, 13.7 mmol) and TBSCl (4.1 mL, 16.44 mmol) inDMF (13 mL) at RT. The reaction was stirred at RT overnight, then wasconcentrated in vacuo. The residue was extracted with DCM (25 mL) andwashed with water (20 mL). The aqueous layer was re-extracted with DCM(25 mL), and the combined organic extracts were washed with brine (20mL), dried (MgSO₄) and concentrated in vacuo. The crude oily product (6g) was chromatographed (120 g SiO₂; continuous gradient from 0-20%,EtOAc in hexane) to afford Part A compound (3.69 g, 86% yield) as acolorless oil. [M+H]⁺ not observed in LC/MS. ¹H-NMR (400 MHz, CDCl₃): δ7.67 (m, 4H), 7.41 (m, 6H), 3.91 (m, 1H), 3.61 (dd, 1H), 3.45 (dd, 1H),2.58 (d, 1H), 1.10 (d, 3H), 1.07 (s, 9H).

A solution of DIAD (0.216 mL, 1.12 mmol) in THF (0.5 mL) was addeddropwise over 3 min to a 0° C. mixture of the Part A compound (304 mg,0.967 mmol), methyl 3-hydroxy-5-(4-(methylsulfonyl)phenoxy)benzoate (240mg, 0.744 mmol) and polymer-supported Ph₃P (1.6 mmol/g load, 1.2 g, 1.92mmol) in 10 mL of THF under Ar. The reaction was allowed to warm to RT.After 3 hours at RT, the reaction was filtered and the resin thoroughlyrinsed with THF and DCM. The combined filtrates were concentrated invacuo. The residue was chromatographed (SiO₂; 40 g; continuous gradientfrom 0-40% EtOAc in hexane) to give partially purified product(contained some reduced DIAD by ¹H-NMR) which was used in the next stepwithout further purification.

LiOH.H₂O (93 mg, 2.22 mmol) was added to a 0° C. mixture of the methylester from above (nominally 0.744 mmol) in 4 mL of THF and 1 mL ofwater. The reaction was allowed to warm to RT overnight. Analytical HPLCindicated that ˜16% of the starting material remained, so more LiOH.H₂O(31 mg) was added. After an additional 4.5 h, the reaction mixture wasconcentrated in vacuo, then was partitioned between water and EtOAc (15mL each). The aqueous layer was extracted with 15 mL of EtOAc. Thecombined organic extracts were washed with 10% aqueous KHSO₄ (10 mL), 10mL each of water and brine, dried (MgSO₄) and concentrated in vacuo togive Part B compound (402 mg, 90% yield), which still contained somereduced DIAD. ¹H NMR (400 MHz, CDCl₃) partial assignments: δ 7.90 (d,2H), 7.63 (d, 4H), 7.46 (s, 1H), 7.30-7.43 (m, 7H), 7.10 (d, 2H), 6.82(s, 1H), 4.58 (m, 1H), 3.77 (dd, 2H), 3.06 (s, 3H), 1.01 (s, 9H).

EDC (26.1 mg, 0.136 mmol) was added to a 0° C. mixture of Part Bcompound (75 mg, 0.124 mmol), HOAT (20.2 mg, 0.149 mmol), diethyl(6-aminopyridin-3-yl)methylphosphonate (39.3 mg, 0.161 mmol) and Et₃N(19 μL, 0.136 mmol) in 1.5 mL of DCM under Ar. After 5 days, LC/MSanalysis showed a ca. 62:9 ratio of desired product to the HOAT ester ofthe Part B acid. After another 24 h, the reaction mixture was dilutedwith 7 mL of DCM and washed with 2 mL each of 0.5N aqueous HCl, water,sat. aqueous NaHCO₃ and brine, dried (MgSO₄) and concentrated in vacuo.The crude product (85 mg) was chromatographed (12 g SiO₂; elution with acontinuous gradient from 0-5% MeOH to DCM) to provide Part C compound(46 mg; 45%) as a colorless oil. [M+H]⁺=831.4; ¹H-NMR (400 MHz, CDCl₃):δ 8.57 (s, 1H), 8.31 (d, 1H), 8.21 (s, 1H), 7.90 (d, 2H), 7.74 (d, 1H),7.63 (m, 4H), 7.32-7.43 (m, 6H), 7.28 (s, 1H), 7.07-7.14 (m, 3H), 6.79(s, 1H), 4.59 (m, 1H), 4.08 (m, 4H), 3.78 (dd, 2H), 3.12 (d, 2H), 3.07(s, 3H), 1.33 (d, 3H), 1.25-1.30 (m, 6H), 1.02 (s, 9H).

To a 0° C. solution of Part C compound (46 mg, 0.0553 mmol) in 1.5 mL ofTHF under Ar was added Bu₄NF (0.11 mL of a 1M solution in THF, 0.11mmol).

The reaction was allowed to warm to RT. After 4 hr, the reaction mixturewas concentrated in vacuo and partitioned between 6 mL of EtOAc and 2 mLof water. The organic extract was washed with 2 mL each of water andbrine, dried (MgSO₄) and concentrated in vacuo. The residue (44 mg) waspurified by preparative reverse phase HPLC on a 30×100 mm PhenomenexAxia Luna 5μ C18 column (linear 20-100% gradient from 90:10:0.1 to10:90:0.1, water:CH₃CN:TFA). The purified material was dissolved in DCM(6 mL) and washed with 2 mL each of sat. aqueous NaHCO₃ and brine, dried(MgSO₄) and concentrated in vacuo to yield the title compound (25 mg;76%) as a colorless oil. [M+H]⁺=593.2; ¹H-NMR (400 MHz, CDCl₃): δ 8.85(s, 1H), 8.31 (d, 1H), 8.17 (s, 1H), 7.92 (d, 2H), 7.72 (d, 1H), 7.34(s, 1H), 7.16 (s, 1H), 7.12 (d, 2H), 6.81 (s, 1H), 4.58 (m, 1H), 4.07(m, 4H), 3.77 (m, 2H), 3.08 (s, 3H), 1.27 (m, 6H).

Example 31

To a RT slurry of 3-amino-1,2,4-triazole (1.0 g, 11.9 mmol) in hexanes(20 mL) was added TMEDA (0.07 g, 0.6 mmol) and di-tert-butyl dicarbonate(3.89 g, 17.8 mmol). The reaction mixture was stirred at RT for 24 h,poured into sat. aqueous NaHCO₃ (150 mL) and the product was extractedwith EtOAc (2×25 mL). The organic extracts were combined, dried (MgSO₄)and concentrated in vacuo. The residue was chromatographed (SiO₂:continuous gradient from 0% EtOAc/Hexane to 100% EtOAc/Hex) to give thedesired Part A compound (1.33 g, 61% yield) as a white solid.[M+H]⁺=185.0; ¹H NMR (400 MHz, CDCl₃): δ 7.48 (s, 1H), 1.66 (s, 9H)

To a 0° C. solution of Part A compound (0.500 g, 2.71 mmol) in DMF (5mL) was added 60% NaH in oil (0.119 g, 2.99 mmol), in 1 portion, and theresultant slurry was stirred at 0° C. for 1 h. ICH₂PO₃Et₂ (0.830 g, 2.99mmol) was added, and the reaction mixture was stirred overnight at RT.The reaction mixture was poured into brine (35 mL); and extracted withEtOAc (4×25 mL); the combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex Luna AXIA 30×100 mm column; detection at 220 nm; flowrate=40 mL/min.; continuous gradient from 100% A to 100% B over 15min.+2 min. hold at 100% B, where A=90:10 H₂O:MeOH and B=90:10 MeOH:H₂O) to provide the Part B compound (0.059 g, 6.5% yield) as a whitesolid. [M+H]=335.1; ¹H NMR (400 MHz, DMSO-d₆):

9.59 (s, 1H), 8.24 (d, J=1.76 Hz, 1H), 4.75 (d, J=11.87 Hz, 2H),4.10-4.00 (m, 4H), 1.42 (s, 9H) 1.21 (t, J=7.03 Hz, 6H).

To a RT solution of Part B compound (0.059 g, 0.177 mmol) in CH₂Cl₂ (1mL) was added TFA (2.04 mL, 3.13 mmol). The reaction mixture was stirredat RT for 2 h, then was concentrated in vacuo. The residue was purifiedby preparative HPLC (Phenomenex Luna 21.2×100 mm column; detection at220 nm; flow rate=20 mL/min.; continuous gradient from 100% A to 100% Bover 15 min.+2 min. hold at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH: H₂O:TFA) to provide Part C compound (0.050 g, 81%yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃)

7.27 (s, 1H), 6.78 (s, 2H), 4.43 (d, J=13.62 Hz, 2H), 4.24-4.15 (m, 4H),1.32-1.38 (m, 6H).

To a RT solution of Example 26 Part C compound (0.023 g, 0.060 mmol) inCH₂Cl₂ (1 mL) were added oxalyl chloride (10.6 μL, 0.121 mmol) and DMF(0.9 μL, 0.012 mmol) and the reaction mixture was stirred at RT for 1 h.Volatiles were removed in vacuo to provide crude Part D compound (0.060g) as a yellow oil.

To a RT solution of crude Part D compound (0.060 g, 0.24 mmol) in CH₂Cl₂(1 mL) were added a solution of Part C compound (0.031 g, 0.090 mmol)and pyridine (0.019 mL, 0.241 mmol) in CH₂Cl₂ (1 mL). The reactionmixture was stirred at RT overnight, then was partitioned between sat.aqueous NaHCO₃ (1 mL) and EtOAc (2 mL); the organic phase was washedwith sat. aqueous NaHCO₃ (1 mL), dried (MgSO₄) and concentrated invacuo. The residue was purified by preparative HPLC (Phenomenex LunaAXIA 21.2×100 mm column; detection at 220 nm; flow rate=40 mL/min.;continuous gradient from 100% A to 100% B over 15 min.+2 min. hold at100% B, where A=90:10 H₂O:MeOH and B=90:10 MeOH:H₂O) to provide thetitle compound (0.007 g, 19.0% yield) as a white solid. [M+H]⁺=597.3; ¹HNMR (400 MHz, CDCl₃):

9.65 (s, 1H), 8.42 (d, J=1.76 Hz 1H), 7.92 (t, J=1.76 Hz, 1H), 7.90 (t,J=1.76 Hz, 7.45 (t, J=1.75 Hz, 1H), 7.32 (t, J=1.76 Hz 1H), 7.15 (t,J=1.76 1H), 7.14 (t, J=1.76 Hz), 6.88 (t, J=2.19 Hz 1H), 4.80-4.75 (m,1H), 4.70 (d, J=13.18 Hz, 2H), 4.29-4.19 (m, 4H), 3.64-3.54 (m, 2H),3.42 (s, 3H), 3.07 (s, 3H), 1.35 (t, J=7.03, 9H).

Example 32

To a 0° C. solution of 1H-pyrazol-3-amine (1.00 g, 12.03 mmol) in DMF(25 mL) was added potassium tert-butoxide (2.70 g, 24.07 mmol) and thereaction mixture was stirred at 0° C. for 1 h. ICH₂PO₃Et₂ (3.35 g, 12.03mmol) was added, and the reaction mixture was stirred at 0° C. for 1.5h, then was allowed to warm to RT and stirred at RT overnight. Volatileswere removed in vacuo, and the residue was partitioned between brine (30mL) and EtOAc (30 mL). The product was extracted with EtOAc (5×30 mL);the combined organic extracts were dried (MgSO₄), and concentrated invacuo. The residue was purified by preparative HPLC (Phenomenex LunaAXIA 5 μm C18 30×100 mm column; detection at 220 nm; flow rate=40mL/min.; continuous gradient from 100% A to 20% B over 25 min.+2 min.hold at 20% B, where A=90:10 H₂O:MeCN and B=90:10 MeCN:H₂O) to providethe Part A compound (0.470 g, 16.8% yield) as a pale yellow oil.[M+H]⁺=233.9; ¹H NMR (400 MHz, CDCl₃):

7.29 (s, 1H), 5.66 (d, J=2.20 Hz, 1H), 4.36 (d, J=11.55 Hz, 2H), 4.10(m, 4H), 3.76 (s, 2H) 1.29 (t, J=7.15 Hz, 6H).

To a RT solution of Example 26 Part C compound (0.16 g, 0.421 mmol) inDMF (8 mL) were added EDAC (0.161 g, 0.841 mmol), HOAT (0.114 g, 0.841mmol), and iPr₂NEt (0.185 mL, 1.05 mmol), and the reaction mixture wasstirred at RT for 30 min. A solution of Part A compound (0.123 g, 0.526mmol) in DMF (2 mL) was added and the reaction mixture was stirred at RTovernight, then poured into H₂O (40 mL). The mixture was extracted withEtOAc (2×15 mL); the combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex Luna 5μ. C18 30×100 mm column; detection at 220 nm; flowrate=40 mL/min.; continuous gradient from 100% A to 1000% B over 25min.+10 min. hold at 100% B, where A=90:10 H₂O:MeCN and B=90:10MeCN:H₂O) to provide the title compound (0.149 g, 59.4% yield) as awhite solid. [M+H]⁺=596.3; ¹H NMR (400 MHz, CDCl₃):

8.98 (s, 1H), 7.92 (t, J=1.65 Hz, J=3.3 Hz 1H), 7.90 (t, J=2.70 Hz,j=2.2 Hz, 1H) 7.47 (d, J=2.2 Hz, 1H), 7.35 (t, J=1.65 Hz, 1H), 7.20 (t,J=2.2 Hz, 1H), 7.14 (t, J=2.75 Hz, J=2.2 Hz, 1H), 7.12 (t, J=2.75 Hz,J=2.20 Hz, 6.90 (d, J=2.20 Hz, 1H), 6.82 (t, J=2.20 Hz, 1H), 4.67-4.59(m, 1H), 4.51 (d, J=12.09 Hz, 2H), 4.13-4.03 (m, 4H), 3.58 (dd, J=10.44Hz, J=6.05 Hz, 1H), 3.51 (dd, J=10.44 Hz, J=3.85 Hz, 1H), 3.40 (s, 3H),3.08 (s, 3H), 1.33 (d, J=6.05 Hz, 3H), 1.27 (t, J=7.14 Hz, 6H).

Example 33

To a solution of methyl 3,5-dihydroxybenzoate (10.0 g, 59.5 mmol) in DMF(60.0 mL) under Ar was added K₂CO₃ (12.4 g, 89.7 mmol) at RT. Benzylbromide (10.0 mL, 84.2 mmol; filtered through basic Al₂O₃ prior to use)was added slowly over 10 min. The reaction mixture was stirred for 12 hat RT and then carefully quenched with sat. aqueous NH₄Cl (50 mL),followed by H₂O (350 mL). The aqueous suspension was extracted withCH₂Cl₂ (1×30 mL, 2×50 mL). The combined organic extracts were washedwith H₂O (100 mL) and brine, dried [MgSO₄] and concentrated in vacuo togive the crude product (27.0 g) as a golden-colored oil. The crudematerial was chromatographed (product eluted during the 30% EtOAc/hexaneportion of a stepwise gradient (10-50% EtOAc/hexane) to yield Part A(i)compound (4.6 g, 30%) as a cream-colored powder.

To a 0° C. solution of Part A(i) compound (1.0 g, 3.9 mmol) in THF (16.8mL) were successively added (R)-(−)-1-methoxy-2-propanol (0.5 g, 5.8mmol) and Ph₃P (1.5 g, 5.8 mmol), followed by slow addition of DIAD (1.1mL, 5.8 mmol). The reaction mixture was warmed to RT and stirred at RTfor 2 days. The reaction mixture was diluted with H₂O and extracted withEt₂O. The organic layer was dried [MgSO₄] and concentrated in vacuo togive a thick, pale, yellow oil. This crude material was chromatographed(product eluted during the 10% EtOAc/hexane portion of a stepwisegradient of 10-30% EtOAc/hexane) to give Part A(ii) compound (1.1 g, 85%yield) as a colorless oil.

A flask containing Part A(ii) compound (1.2 g, 3.6 mmol) in MeOH (45.4mL) was evacuated and flushed with Ar. In one portion, 10% Pd/C (0.38 g,0.36 mmol) was added. The mixture was stirred under an atmosphere of H₂for 12 h at RT, then was filtered through Celite®, which was washed withEtOAc. The combined filtrates were concentrated in vacuo to give PartA(iii) compound (0.81 g, 93% yield) as a yellow oil.

To a 0° C. solution of Part A(iii) compound (0.14 g, 0.59 mmol) in THF(2.9 mL) were added Ph₃P (0.4 g, 1.3 mmol) and (R)-1-phenylpropan-2-ol(0.2 g, 1.3 mmol) under Ar. The reaction mixture was stirred for 5 minat 0° C., then DIAD (0.3 mL, 1.3 mmol) was added dropwise. The reactionmixture was stirred at RT for 12 h, then was diluted with H₂O andextracted with EtOAc (2×). The combined organic extracts were washedwith 1N aqueous NaOH and brine, dried [MgSO₄] and concentrated in vacuoto give a pale yellow oil (1.0 g). This crude material waschromatographed (product eluted during the 10% EtOAc/hexane portion of astepwise gradient from 5-20% EtOAc/hexane) to give Part A(iv) compound(0.17 g, 81% yield) as a near-colorless oil.

To a solution of Part A(iv) compound (0.17 g, 0.5 mmol) in THF (1.8 mL)and H₂O (0.6 mL) was added LiOH.H₂O (0.02 g, 0.52 mmol) at RT. Thereaction mixture was stirred at 45° C. for 1 h; an additional portion ofLiOH.H₂O was added, and stirring was continued at 45° C. The startingmaterial was consumed after 6 h, and the reaction was cooled to RT.Volatiles were removed in vacuo, and the remaining aqueous layer wasacidified to pH 2 with 0.5 N aqueous HCl, then was extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried[MgSO₄] and concentrated in vacuo to give crude Part A(v) compound (0.16g, 86%) as a pale-yellow oil.

To a RT solution of Part A(v) compound (0.030 g, 0.087 mmol) in DMF (1.5mL) was added EDAC (0.033 g, 0.174 mmol), HOAt (0.024 g, 0.174 mmol),and DIEA (0.038 mL, 0.218 mmol). The reaction mixture was stirred at RTfor 30 min, after which a solution of Example 32 Part A compound (0.025g, 0.109 mmol) in DMF (0.5 mL) was added. The reaction mixture wasstirred at RT overnight, then was poured into water (7 mL); the mixturewas extracted with EtOAC (2×10 mL). The combined organic extracts weredried (MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex Luna AXIA 100A 5μ. C18 column; detection at220 nm; flow rate=40 mL/min.; continuous gradient from 100% A to 100% Bover 25 min.+2 min. hold at 100% B, where A=90:10 H₂O:MeCN and B=90:10MeCN:H₂O) to provide the title compound (0.027 g, 56.3% yield) as aclear oil. [M+H]⁺=560.4; ¹H NMR (400 MHz, CDCl₃):

8.59 (s, 1H), 7.44-7.46 (m, 1H), 7.32-7.19 (m, 5H), 7.00 (t, J=1.65 Hz,1H), 6.97 (t, J=2.2 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.63 (t, J=2.2 Hz,1H), 4.65-4.53 (m, 2H), 4.44 (d, J=11.54 Hz, 2H), 4.14-4.04 (m, 4H),3.56 (dd, J=9.9 Hz, J=5.5 Hz, 1H), 3.49 (dd, J=9.89 Hz, J=3.84 Hz, 1H),3.41 (s, 3H), 3.06 (dd, J=13.74 Hz, J=6.04 Hz, 1H), 2.85 (dd, J=13.74Hz, J=6.04 Hz, 1H), 1.26 (m, 12H).

Example 34

To a 0° C. solution of 3,5-bis(trifluoromethyl)benzoic acid (129 mg,0.50 mmol) in CH₂Cl₂ (1 mL) was added oxalyl chloride (0.375 mL, 0.75mmol, 2M in CH₂Cl₂) and DMF (1 drop). The reaction was stirred at 0° C.for 30 min and was then warmed to RT and was stirred for 4 h. Themixture was concentrated in vacuo. To a solution of the acid chlorideresidue in CH₂Cl₂ (3 mL) was added 5-bromopyrazin-2-amine (130 mg, 0.75mmol) and pyridine (0.061 mL, 0.75 mmol). The reaction was stirred at RTfor 18 h and was diluted with CH₂Cl₂ (6 mL), and was washed with 0.5 Naqueous HCl (1 mL, 2×), water (1 mL), sat. aqueous NaHCO₃ (1 mL), andBrine. The organic layer was dried (MgSO₄), filtered, and concentratedin vacuo. The residue was chromatographed (SiO₂) to provide the Part Acompound (40 mg, 19% yield) as a white solid.

THF (degassed)(0.40 mL) was added to Part A compound (25.0 mg; 0.060mmol) and (Ph₃P)₄Pd^(o) (13.9 mg; 0.012 mmol). H(O)P(OEt)₂ (9.33 μL;0.072 mmol) was added followed by TEA (11.7 μL; 0.084 mmol). Thereaction mixture was heated at 85° C. for 5 h, then was cooled to RT andpartitioned between EtOAc (3 mL) and brine (3 mL). The organic phase wasdried (MgSO₄) and concentrated in vacuo. The crude product was purifiedby preparative HPLC(YMC reverse phase ODS-A-5 μm 30×100 mm column; flowrate=40 mL/min, 45 to 100% solvent B over 12 min, hold to 15 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to give the title compound (11.6 mg; 41%) as a light yellow solid.[M+H]⁺=472.2; ¹H NMR (400 MHz, CDCl₃): δ 1.37 (t, 6H), 4.27 (m, 4H),8.12 (s, 1H), 8.53 (s, 2H), 8.82 (s, 1H), 9.53 (s, 1H), 9.80 (s, 1H).

Example 35

DIPEA (66 μL; 0.378 mmol) was added to a stirred solution of Example 1Part D compound (80 mg; 0.270 mmol), 2-amino-5-formylthiazole (43.3 mg;0.338 mmol) and HOAt (44.0 mg; 0.324 mmol) in DMF (1.0 mL). EDAC (62.0mg; 0.324 mmol) was added. After 3 h at RT, the reaction mixture waspartitioned between EtOAc (8 mL) and H₂O (8 mL). The organic phase waswashed with 1N aqueous HCl (5 mL), sat. aqueous NaHCO₃ (5 mL) and brine(5 mL), dried (MgSO₄) and concentrated in vacuo. The crude product waschromatographed (SiO₂; continuous gradient from 0 to 100% EtOAc inhexanes over 11 min, hold at 100% EtOAc for 4 min) to give Part Acompound (81 mg; 74%) as a foam.

CH₂(PO₃Et)₂ (59.4 μL; 0.239 mmol) was added to a mixture of powderedLiCl (10.13 mg; 0.239 mmol) in CH₃CN (1.0 mL). DBU (35.7 μL; 0.239 mmol)was added followed by a solution of Part A compound (81.0 mg; 0.199mmol) in CH₃CN (1.0 mL). After 24 h at RT more CH₂(PO₃Et)₂ (9.92 μL;0.040 mmol), DBU (5.96 μL; 0.040 mmol) and LiCl (1.7 mg; 0.040 mmol)were added. After 72 h the reaction mixture was concentrated in vacuo.The residue was partitioned between EtOAc (8 mL) and 0.2 N aqueous HCl(8 mL). The organic phase was washed with brine (6 mL), dried (MgSO₄)and concentrated in vacuo. The crude product was chromatographed (SiO₂;continuous gradient from 0% to 100% EtOAc in hexanes over 6 min,switched to 2% MeOH in EtOAC and held for 8 min) to give the titlecompound (67 mg; 62%) as a colorless solid. [M+H]⁺=541.1; ¹H NMR (400MHz, CDCl₃)(19:1, E/Z): δ 1.15 (m, 2H), 1.37 (m, 6H), 1.48 (m, 2H), 1.66(m, 3H), 1.78 (m, 2H), 1.92 (m, 1H), 2.27 (m, 1H), 3.03 (s, 3H), 4.12(m, 5H), 5.88 (dd, J=17.3 Hz, 1H), 7.58 (s, 1H), 7.66 (d, 2H), 7.89 (d,2H), 8.14 (dd, J=17.1 Hz, 1H).

Example 36

20% Pd(OH)₂ (16 mg) was added to a solution of Example 35 compound (35mg; 0.065 mmol) in MeOH (0.40 mL). A H₂ (g) atmosphere was introducedvia balloon. After 48 h of stirring, the reaction mixture was filtered.The catalyst was rinsed with MeOH (1.5 mL), EtOAc (1.5 mL) and CHCl₃(1.5 mL) and the combined filtrates were concentrated in vacuo. Thecrude product was purified by preparative HPLC(YMC reverse phase ODS-A-5u 20×100 mm column; flow rate=20 mL/min, 15 to 100% solvent B over 10min, hold to 12 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA) to provide the title compound (18 mg; 51%).[M+H]⁺=543.2; ¹H NMR (400 MHz, CD₃OD):

1.19 (m, 2H), 1.29 (t, 6H), 1.51 (m, 2H), 1.64 (m, 3H), 1.80 (m, 3H),2.17 (m, 3H), 3.05 (m, 2H), 3.09 (s, 3H), 3.96 (t, 1H), 4.07 (m, 4H),7.20 (s, 1H), 7.67 (d, 2H), 7.92 (d, 2H).

Example 37

DIPEA (387 μL; 2.22 mmol) was added to a cold (0° C.) solution ofExample 26 Part C compound (704 mg; 1.85 mmol), Example 13 Part Ecompound (556 mg; 2.22 mmol) and HOAt (302 mg; 2.22 mmol) in DMF (7.4mL). EDAC (426 mg; 2.22 mmol) was added. After 24 h at RT, the reactionmixture was partitioned between EtOAc (100 mL) and H₂O (75 mL). Theorganic phase was washed with 0.5 N aqueous HCl (50 mL), sat. aqueousNaHCO₃ (50 mL) and brine (50 mL), dried (MgSO₄) and concentrated invacuo. The crude product was purified by preparative HPLC(YMC reversephase ODS-A-5 u 30×250 mm column; flow rate=30 mL/min, 15 to 100%solvent B over 25 min, hold to 30 min, where solvent A=90:10:0.1H₂O:CH₃CN:TFA and solvent B=90:10:0.1 CH₃CN:H₂O:TFA). The product waspurified by preparative HPLC a second time using the same conditions butusing MeOH instead of CH₃CN to give the title compound (778 mg; 69%) asa white foam. [M+H]⁺=613.2; ¹H NMR (400 MHz, CDCl₃): δ 1.26 (t, 6H),1.35 (d, 3H), 3.08 (s, 3H), 3.34 (d, 2H), 3.41 (s, 3H), 3.55 (m, 2H),4.08 (m, 4H), 4.69 (m, 1H), 6.88 (s, 2H), 7.14 (d, 2H), 7.30 (s, 1H),7.48 (s, 1H), 7.92 (d, 2H).

Example 38

The title compound (39 mg; 78%; yellow solid) was synthesized fromExample 15 Part D compound employing the procedure described for Example37. [M+H]⁺=613.3; ¹H NMR (400 MHz, CDCl₃): δ 1.34 (m, 9H), 3.08 (s, 3H),3.28 (d, 2H), 3.41 (s, 3H), 3.59 (m, 2H), 4.15 (m, 4H), 4.84 (m, 1H),6.93 (s, 1H), 7.15 (d, 2H), 7.34 (d, 1H), 7.40 (s, 1H), 7.63 (s, 1H),7.92 (d, 2H).

Example 39

A solution of Example 13 Part B compound (0.94 g; 4.08 mmol) in DCM (8mL) was added dropwise to a 0° C. solution of Dess-Martin periodinane(1.82 g; 4.28 mmol) in DCM (8 mL). After 20 h at RT, the reaction wasdiluted with DCM (4 mL) and 1.0 N aqueous NaOH (6 mL). After stirringfor 10 min, the mixture was filtered through Celite®. The organic phasewas washed with brine (10 mL), dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; continuous gradient from 0 to 50%EtOAc in hexanes over 12 min, hold at 50% EtOAc in hexanes for 8 min) togive Part A compound (0.65 g; 70%) as a white solid.

TFA (2.0 mL) was added to a 0° C. solution of Part A compound (0.64 g;2.80 mmol) in DCM (4.0 mL). After 20 h at RT the reaction mixture wasconcentrated in vacuo. The residue was partitioned between EtOAc (10 mL)and sat. aqueous NaHCO₃ (8 mL). The aqueous phase was isolated andextracted with EtOAc (5×8 mL). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo to give Part B compound (0.30 g; 83%)as a yellow solid.

DIPEA (88.7 μL; 0.509 mmol) was added to a stirred solution of Example 1Part D compound (130 mg; 0.439 mmol), Part B compound (67.4 mg; 0.526mmol) and HOAt (69.3 mg; 0.509 mmol) in DMF (1.5 mL). EDAC (97.6 mg;0.509 mmol) was added. After 20 h stirring at RT the reaction mixturewas partitioned between EtOAc (12 mL) and H₂O (12 mL). The organic phasewas washed with 0.5 N aqueous HCl (8 mL), sat. aqueous NaHCO₃ (8 mL) andbrine (8 mL), dried (MgSO₄) and concentrated in vacuo. The crude productwas chromatographed (SiO₂; continuous gradient from 0 to 80% EtOAc inhexanes over 13 min, hold at 80% EtOAC in hexanes for 3 min) to givePart C compound (100 mg; 56%) as a yellow foam.

H(O)P(OEt)₂ (10.0 μL; 0.078 mmol) was added to Part C compound (30.0 mg;0.074 mmol) followed by pyridine (6.6 μL; 0.081 mmol). The reactionmixture was heated at 70° C. for 5 h, then cooled to RT. After 48 h moreH(O)P(OEt)₂ (10.0 μL; 0.078 mmol) and pyridine (10.0 mL; 0.123 mmol)were added and heating at 70° C. was continued. After 7 h the reactionwas cooled to RT and diluted with EtOAc (3 mL), washed with 1.0 Naqueous HCl (1.5 mL) and brine (1.5 mL), dried (MgSO₄) and concentratedin vacuo. The crude product was chromatographed (SiO₂; continuousgradient from 0 to 100% EtOAc in hexanes over 3 min, switch to 3% MeOHin EtOAc and hold for 8 min) The product was then purified bypreparative HPLC(YMC reverse phase ODS-A-5 u 20×100 mm column; flowrate=20 mL/min, 10 to 100% solvent B over 10 min, hold to 12 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to give the title compound (14 mg; 35%) as a light yellow solid(diastereomeric mixture). [M+H]⁺=545.2; ¹H NMR (400 MHz, CDCl₃):

1.13 (m, 2H), 1.28 (m, 6H), 1.49 (m, 2H), 1.60 (m, 3H), 1.76 (m, 2H),1.96 (m, 1H), 2.23 (m, 1H), 3.04 (s, 3H), 4.01 (t, 1H), 4.16 (m, 4H),5.18 (dd, 1H), 7.03 (d, 1H), 7.65 (d, 2H), 7.90 (d, 2H).

Example 40

Oxalyl chloride (2.0 M in DCM) (45.0 μL; 0.091 mmol) was added to asolution of Oxalyl chloride (2.0 M in DCM) (45.0 μL; 0.091 mmol) wasadded to a solution of Example 26 Part C compound (23.0 mg; 0.060 mmol)in DCM (0.20 mL). DMF (5 μL) was added. Gas evolution occurred. Thereaction mixture was stirred at RT for 1 h, then was concentrated invacuo. The residue was stripped from DCM (2×1 mL). The crude acidchloride was dissolved in DCM (0.25 mL). Example 7 Part B compound (16.2mg; 0.066 mmol) was added followed by pyridine (14.6 μL; 0.180 mmol).After 20 h at RT the reaction was concentrated in vacuo. The residue waspartitioned between EtOAc (4 mL) and 0.5 N aqueous HCl (3 mL). Theorganic phase was washed with sat. aqueous NaHCO₃ (3 mL) and brine (3mL), dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by preparative HPLC(YMC reverse phase ODS-A-5 u 30×100 mmcolumn; flow rate=40 mL/min, 15 to 100% solvent B over 12 min, hold to14 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (13 mg; 36%) as a white solid.[M+H]⁺=608.2; ¹H NMR (400 MHz, CDCl₃): δ 1.32 (m, 9H), 3.07 (s, 3H),3.40 (s, 3H), 3.44 (d, 2H), 3.57 (q, 2H), 4.13 (m, 4H), 4.63 (m, 1H),6.88 (s, 1H), 7.16 (d, 2H), 7.19 (s, 1H), 7.35 (s, 1H), 7.93 (d, 2H),8.32 (s, 1H), 8.53 (s, 1H), 9.59 (s, 1H).

Example 41

nBuLi (575 μL of a 1.6 M solution in hexanes; 0.920 mmol) was addeddropwise to a cold (−78° C.) solution of Me(O)P(OEt)₂ (134 μL; 0.920mmol) in THF (0.30 mL). After 20 min a solution of Example 39 Part Acompound (100 mg; 0.438 mmol) in THF (0.70 mL) was added dropwise. After1 h at −78° C., the reaction was quenched by addition of AcOH (63 μL;1.10 mmol). The reaction was warmed to RT and concentrated using astream of Ar. The residue was partitioned between EtOAc (5 mL) and brine(4 mL). The organic phase was dried (MgSO₄) and concentrated in vacuo.The crude product was chromatographed (SiO₂; continuous gradient from 0to 100% EtOAc in hexanes over 8 min, switch to 4% MeOH in EtOAc and holdfor 6 min) to give Part A compound (104 mg; 62%) as a syrup.

HCl (100 μL of a 4.0 N solution in 1,4 dioxane) was added to Part Acompound (104 mg; 0.273 mmol). After 20 h, the reaction mixture wasconcentrated in vacuo to give Part B compound (64 mg; 75%) as an oil,which was used in the next step without further purification.

DIPEA (56.0 μL; 0.324 mmol) was added to a stirred solution of Example 1Part D compound (32.0 mg; 0.108 mmol), Part B compound (48.0 mg; 0.151mmol) and HOAt (16.9 mg; 0.124 mmol) in DMF (0.42 mL). EDAC (23.8 mg;0.124 mmol) was added. After 2 h at RT the reaction mixture waspartitioned between EtOAc (4 mL) and 0.5 N aqueous HCl (3 mL). Theorganic phase was washed with sat. aqueous NaHCO₃ (3 mL) and brine (3mL), dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by preparative HPLC(YMC reverse phase ODS-A-5 u 20×100 mmcolumn; flow rate=20 mL/min, 15 to 100% solvent B over 12 min, hold to14 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1

MeOH:H₂O:TFA) to give the title compound (27 mg; 45%) as a white solid.[M+H]⁺=559.3; ¹H NMR (400 MHz, CDCl₃): δ 1.15 (m, 2H), 1.27 (m, 3H),1.35 (t, 3H), 1.49 (m, 2H), 1.62 (m, 3H), 1.78 (m, 2H), 1.95 (m, 1H),2.25 (m, 1H), 2.41 (m, 2H), 3.04 (s, 3H), 4.03 (t, 1H), 4.16 (m, 4H),5.19 (t, 1H), 6.93 (s, 1H), 7.65 (d, 2H), 7.90 (d, 2H).

Example 42

To a cold (internal temperature maintained at 5° C.) solution of Example26A (3.7 g, 11.5 mmol), (R)-(−)-1-benzyloxy-2-propanol (2.5 g, 15 mmol),and polymer-supported Ph₃P (30 g of 1 mmol/g, 30 mmol) in THF (150 mL)under N₂ (g) was added dropwise over 15 min a solution of DIAD (3.4 mL,17.3 mmol). The reaction mixture was warmed to RT and was stirred for 18h, then filtered. The solids were thoroughly washed with THF and CH₂Cl₂.The combined filtrates were concentrated in vacuo. The mixture waschromatographed (SiO₂; EtOAc/Hexane 1:1) to give Part A compound (6.0 g,110%) as a colorless oil. [M+H]=471.2; ¹H NMR (400 MHz, CDCl₃) δ 7.90(2H, d, J=8.79 Hz), 7.48 (1H, s), 7.27-7.37 (6H, m), 7.09 (2H, d, J=8.79Hz), 6.83-6.89 (1H, m), 4.60-4.69 (1H, m), 4.58 (2H, s), 3.90 (3H, s),3.54-3.70 (2H, m), 3.06 (3H, s), 1.34 (3H, d, J=6.15 Hz).

A solution of Part A (6 g, 13 mmol), LiOH (1.6 g, 39 mmol), and H₂O (50mL) in THF (20 mL) was stirred at RT for 3 h, then was concentrated invacuo. The aqueous solution was washed with Et₂O (15 mL×4), acidified topH 4 with concentrated HCl, and was extracted with EtOAc (50 mL). Theorganic layer was washed with H₂O, dried (MgSO₄), filtered, andconcentrated in vacuo to give Part B compound (5 g, 95%) as a whitesolid. [M+H]=457.2; ¹H NMR (400 MHz, CDCl₃) δ 7.91 (2H, d, J=8.79 Hz),7.52 (1H, s), 7.27-7.38 (6H, m), 7.11 (2H, d, J=8.79 Hz), 6.90 (1H, t,J=2.20 Hz), 4.61-4.70 (1H, m), 4.59 (2H, s), 3.56-3.70 (2H, m), 3.07(3H, s), 1.35 (3H, d, J=6.59 Hz).

DIPEA (22.0 μL; 0.127 mmol) was added to a 0° C. solution of Part Ccompound (50 mg; 0.110 mmol), Example 13 Part E compound (33.0 mg; 0.131mmol) and HOAt (17.0 mg; 0.127 mmol) in DMF (0.44 mL), followed by EDAC(24.0 mg; 0.127 mmol). After 24 h at RT the reaction mixture waspartitioned between EtOAc (7 mL) and 0.5 N aqueous HCl (5 mL). Theorganic phase was washed with sat. aqueous NaHCO₃ (5 mL) and brine (5mL), dried (MgSO₄) and concentrated in vacuo. The crude product waschromatographed (SiO₂; continuous gradient from 0 to 100% EtOAc inhexanes over 12 min, hold at 100% EtOAc for 4 min) The product wasfurther purified by dissolving in MeOH (1 mL) and loading onto a 0.5 gSAX (strong anion exchange) column. The column was eluted with MeOH (4mL). The filtrate was concentrated to give the title compound (50 mg;67%) as a light yellow residue. [M+H]⁺=689.3; ¹H NMR (400 MHz, CDCl₃): δ1.26 (t, 6H), 1.34 (m, 3H), 3.08 (s, 3H), 3.34 (d, 2H), 3.62 (m, 2H),4.06 (m, 4H), 4.58 (s, 2H), 4.68 (m, 1H), 6.85 (s, 1H), 6.88 (s, 1H),7.14 (d, 2H), 7.20 (s, 1H), 7.27 (m, 5H), 7.39 (s, 1H), 7.92 (d, 2H).

Example 43

Note: The following procedure was adapted from WO 2006/016178 and WO2006/016174.

To a 0° C. suspension of NH₄Cl (8.44 g, 63.3 mmol) in DCM (40 mL) wasadded ethyl 2-chloro-2-oxoacetate (5.53 mL, 49.7 mmol) over 10 min. Thereaction was stirred at 0° C. for 30 min. Cyclopropyl phenyl sulfide(6.5 mL, 45.2 mmol) was then added over a period of 45 min, keeping thetemperature at 0° C. [Note: when sulfide was added, reaction immediatelyturned deep purple/red in color]. The reaction was allowed to warm to RTand was stirred at RT for 18 h. Ice water (100 mL) was slowly added tothe mixture at 0° C. The organic phase was washed with H₂O (2×), sat.aqueous NaHCO₃ (2×), and again with H₂O. The organic layer was dried[MgSO₄] and concentrated in vacuo to give crude Part A(i) compound (6.1g, 54%) as a yellow oil.

A solution of Part A(i) compound (6.1 g, 24.37 mmol) in toluene (50 mL)was heated to 50° C. with stirring. 3N aqueous NaOH (9.75 mL, 29.2 mmol)was added dropwise while keeping the temperature at 60° C. After theaddition was complete, the reaction was stirred at 50° C. for 4 h, thenwas cooled to RT and neutralized by cautious addition of conc HCl (0.821mL, 26.8 mmol). The reaction was stirred at RT for 18 h. The organicphase was concentrated in vacuo to give crude Part A(ii) compound (6.0g, 111%) as a yellow solid.

To NH₂NH₂.H₂O (5.89 mL, 121 mmol) at −78° C. was added Part A(ii)compound (5.4 g, 24.30 mmol) in one portion, and the reaction was heatedto 80° C. with stirring, then was cooled to RT. KOH (0.818 g, 14.58mmol) was added; the reaction was stirred at RT for several minutes, andthen a second portion of KOH (0.818 g, 14.58 mmol) was added. Thereaction was stirred at RT for several minutes, and then a third portionof KOH (0.818 g, 14.58 mmol) was added. The reaction again was stirredat RT for several minutes, and a fourth portion of KOH (0.818 g, 14.58mmol) was added. The reaction was then heated at 100° C. with stirringfor 18 h. The reaction was cooled to RT and diluted with H₂O. Thereaction mixture was partitioned between Et₂O and H₂O. The layers wereseparated, and the aqueous layer was transferred to a round bottomflask. The organic layer was washed with H₂O, and the combined aqueouslayers were treated with heptane (˜50 mL), and the mixture was stirredvigorously. The stirred solution was treated dropwise with concentratedHCl (11.66 mL, 384 mmol) over 30 min at 0° C. The suspension was warmedto RT and was stirred at RT for several hours. A yellow precipitateformed and was filtered off; this material was washed with 1N aqueousHCl and heptane, then was dried in vacuo for 48 h. Part A(iii) compound(3.7 g, 73% yield) was thus isolated as a pale yellow solid.

Part A(iii) compound was stripped from toluene (2×). To a −10° C.mixture of Part A(iii) compound (3.7 g, 17.76 mmol) and K₂CO₃ (7.37 g,53.3 mmol) in anhydrous acetone (50 mL) was added dropwisetrimethylacetyl chloride (2.297 mL, 18.65 mmol) while maintaining thetemperature at −10° C. The reaction was stirred at −10° C. for 30 min,then warmed to 0° C. for 1 h and finally warmed to RT for 30 min. Themixture was recooled to −10° C. and was treated with(1R,2R)-(−)-pseudoephedrine (4.40 g, 26.6 mmol). The reaction wasstirred at −10° C. for 1 h, then was warmed to 25° C. and stirred for 18h at 25° C. The reaction was quenched with H₂O (25 mL) and extractedwith EtOAc. The organic phase was washed with 1N aqueous HCl, dried(MgSO₄) and concentrated in vacuo to give crude Part D compound. CrudePart D compound was dissolved in CH₂Cl₂ and chromatographed (SiO₂; 120g; gradient from 30% EtOAc/Hexane to 100% EtOAc). The combined fractionswere concentrated in vacuo to give Part A(iv) compound (1.16 g, 18.4%yield) as a white solid.

To a solution of tetrahydropyran-4-MeOH (5.0 g, 43 mmol) in CH₂Cl₂ (30mL) was added Et₃N (7.2 mL, 51.6 mmol). The mixture was cooled to 0° C.,and methanesulfonyl chloride (4.0 mL, 51.6 mmol) was added. The mixturewas stirred at 0° C. for several hours, then was slowly warmed to RT.The reaction was stirred at RT for 18 h, then was concentrated in vacuo.The residue was taken up in EtOAc and was washed with sat. NaHCO₃. Theorganic layer was dried [MgSO₄] and concentrated in vacuo to give themesylate Part A(v)(a) compound (8.3 g, quantitative yield) as a white,needle-like solid.

A mixture of the mesylate Part A(v)(a) compound (8.3 g, 43.0 mmol) andNaI (12.8 g, 85.5 mmol) was refluxed at 65° C. in acetone (100 mL) for18 h, then was cooled to RT and filtered. The filter cake was washedwith acetone. The combined filtrates were concentrated in vacuo, and theresidue was partitioned between Et₂O and water. The aqueous layer wasextracted with Et₂O (3×). The combined organic extracts were washed with10% aqueous Na₂S₂O₃ and water, dried [MgSO₄] and concentrated in vacuoto give Part A(v)(b) compound (7.1 g, 74% yield) as a yellow oil.

All starting materials were evaporated with toluene several times andall glassware was dried in an oven overnight. To a −78° C. solution ofLiHMDS (5.91 mL, 5.91 mmol) in THF (15 mL) was added dropwise a solutionof Part A(iv) compound (1.0 g, 2.81 mmol) in THF (15 mL) over 15 min.The reaction was stirred at −78° C. for 15 min, then was warmed to 0° C.for 45 min and recooled to −78° C. Distilled DMPU (0.714 mL, 5.91 mmol)was added and the reaction was stirred at −78° C. for ˜15 min, afterwhich Part A(v) iodide (0.954 g, 4.22 mmol) was added. The reaction wasstirred at −78° C. for 1 h, then was slowly warmed to RT and stirred for18 h. The reaction was quenched with sat. aqueous NH₄Cl (˜10 mL) anddiluted with EtOAc. The mixture was washed with H₂O. The aqueous layerwas extracted with EtOAc, and the combined organic extracts were washedwith brine, dried [MgSO₄] and concentrated in vacuo to give Part A(vi)compound (1.3 g, 100%) as a yellow oil.

A solution of Part A(vi) compound (1.3 g, 2.87 mmol) and 9N concentratedH₂SO₄ (10.4 mL, 94 mmol) in dioxane (20 mL) was refluxed at 110° C. for18 h, then was cooled to RT. The solution was diluted with EtOAc (50 mL)and washed with H₂O (40 mL×2) and brine (20 mL). The organic layer wasdried [MgSO₄] and concentrated in vacuo to give Part A(vii) compound(1.17 g, 133% yield) as a yellow, sticky oil.

To a solution of Part A(vii) compound (0.9 g, 2.94 mmol) in isopropanol(20 mL) and water (10 mL) was added oxone (4.15 g, 6.76 mmol). Thereaction was stirred at RT for 18 h, then was filtered, and the filtratewas concentrated in vacuo. The residue was taken up in EtOAc and waswashed with H₂O and brine. The organic layer was dried [MgSO₄] andconcentrated in vacuo to give Part A(viii) compound (0.9 g, 91% yield)as a pale yellow foam.

Oxalyl chloride (58.0 μL of a 2.0 M solution in DCM; 0.116 mmol) wasadded to a solution of Part A compound (26.0 mg; 0.077 mmol) in DCM(0.25 mL). DMF (5 μL) was added. Gas evolution occurred. The reactionmixture was stirred at RT for 1 h, then was concentrated in vacuo. Theresidue was stripped from DCM (2×1 mL). The crude acid chloride wasdissolved in DCM (0.32 mL). Example 13 Part E compound (23.0 mg; 0.092mmol) was added followed by pyridine (18.7 μL; 0.231 mmol). After 20 hat RT the reaction was concentrated in vacuo. The residue waspartitioned between EtOAc (4 mL) and 0.5 N aqueous HCl (3 mL). Theorganic phase was washed with sat. aqueous NaHCO₃ (3 mL) and brine (3mL), dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by preparative HPLC(YMC reverse phase ODS-A-5 μm 30×100 mmcolumn; flow rate=40 mL/min, 15 to 100% solvent B over 16 min, hold to20 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (17 mg; 39%) as a light yellowsolid. [M+H]⁺=571.4; ¹H NMR (400 MHz, CDCl₃): δ 1.04 (m, 2H), 1.33 (m,11H), 1.63 (m, 2H), 1.87 (m, 1H), 2.21 (m, 1H), 2.46 (m, 1H), 3.28 (m,4H), 3.92 (m, 2H), 4.02 (t, 1H), 4.11 (m, 4H), 6.88 (d, 1H), 7.61 (d,2H), 7.88 (d, 2H).

Example 44

The title compound (22 mg; 51%; light yellow solid) was synthesized fromExample 7 Part B compound and Example 43 Part A(viii) compound employingthe procedure for the synthesis of Example 43 compound. [M+H]⁺=566.4; ¹HNMR (400 MHz, CDCl₃): δ 1.05 (m, 2H), 1.34 (m, 10H), 1.48 (m, 1H), 1.67(m, 2H), 1.79 (m, 1H), 2.22 (m, 1H), 2.46 (m, 1H), 3.35 (m, 4H), 3.92(d, 2H), 4.04 (t, 1H), 4.14 (m, 4H), 7.62 (d, 2H), 7.85 (d, 2H), 8.20(s, 1H), 9.34 (s, 1H), 9.36 (s, 1H).

Example 45

(iPrO)₃P (2.02 mL; 8.20 mmol) was added to a vessel containing Example13 Part C compound (600 mg; 2.05 mmol). The reaction vessel was cappedand the mixture was heated at 85° C. for 16 h, then cooled to RT. Thesolution was directly chromatographed (SiO₂; continuous gradient from 0to 100% EtOAc in hexanes over 7 min, switched to 4% MeOH in EtOAc andheld for 12 min) to give Part A compound (607 mg; 78%) as a viscoussolid.

TFA (2.0 mL) was added to a 0° C. solution of Part A compound (559 mg;1.48 mmol) in DCM (4 mL). The reaction mixture was allowed to warm to RTand stirred at RT for 2 h, then was concentrated in vacuo. The residuewas partitioned between EtOAc (15 mL) and sat. aqueous NaHCO₃ (10 mL).The aqueous phase was extracted with EtOAc (10 mL). The combined organicextracts were washed with brine (10 mL), dried (MgSO₄) and concentratedin vacuo to give Part B compound (0.41 g; 100%) as a yellow solid.

DIPEA (81.3 μL; 0.467 mmol) was added to a solution of Part B compound(135.6 mg; 0.487 mmol), Example 26 Part C compound (154.5 mg; 0.406mmol) and HOAt (63.6 mg; 0.467 mmol) in DMF (1.5 mL). EDAC (89.5 mg;0.467 mmol) was added. After 48 h at RT the reaction mixture waspartitioned between EtOAc (15 mL) and H₂O (12 mL). The organic phase waswashed with 0.5 N aqueous HCl (10 mL), sat. aqueous NaHCO₃ (10 mL) andbrine (10 mL), dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by preparative HPLC(YMC reverse phase ODS-A-5 u30×250 mm column; flow rate=30 mL/min, 20 to 100% solvent B over 18 min,held to 25 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (0.24 g; 92%) as alight yellow solid. [M+H]⁺=641.3; ¹H NMR (400 MHz, CDCl₃):

1.25 (m, 6H), 1.31 (m, 9H), 3.08 (s, 3H), 3.27 (d, 2H), 3.41 (s, 3H),3.58 (m, 2H), 4.71 (m, 2H), 4.80 (m, 1H), 6.92 (s, 1H), 6.99 (s, 1H),7.15 (d, 2H), 7.37 (s, 1H), 7.58 (s, 1H), 7.92 (d, 2H).

Example 46

A mixture of 10% Pd/C (100 mg) and Example 42 Part B compound (1.03 g;2.26 mmol) in EtOAc (6 mL) was stirred under an H₂ atmosphere for 8 h,after which the reaction mixture was filtered. The catalyst was rinsedwith MeOH (10 mL) and the combined filtrates were concentrated in vacuoto give Part A compound (0.82 g; 99%).

A solution of TBSCl (1.01 g; 6.71 mmol) in DMF (6 mL) was added to PartA compound (0.82 g; 2.24 mmol), followed by imidazole (0.91 g; 13.43mmol). After 20 h the reaction mixture was partitioned between EtOAc (50mL) and sat. aqueous NH₄Cl (50 mL). The organic phase was washed withsat. aqueous NH₄Cl (25 mL) and brine (25 mL), dried (MgSO₄) andconcentrated in vacuo. The crude product was chromatographed (SiO₂;continuous gradient from 0 to 100% EtOAc in hexanes over 14 min, hold at100% EtOAc for 4 min) to give Part B compound (725 mg; 68%) as a whitefoam.

DIPEA (14.5 μL; 0.083 mmol) was added to a RT solution of Part Bcompound (30.8 mg; 0.064 mmol), Example 13 Part E compound (21.6 mg;0.086 mmol) and HOAt (10.9 mg; 0.080 mmol) in DMF (0.33 mL). EDAC (15.3mg; 0.080 mmol) was then added. After 48 h at RT the reaction mixturewas partitioned between EtOAc (3 mL) and H₂O (3 mL). The organic phasewas washed with brine (30 mL), dried (MgSO₄) and concentrated in vacuoto give Part C compound (53 mg; 100%) as a syrup. The crude product wasused in the next step without further purification.

TBAF (1.0 M in THF) (152 μL; 0.152 mmol) was added to a 0° C. solutionof Part C compound (54 mg; 0.76 mmol) in THF (0.22 mL). The reaction wasallowed to warm to RT and stirred for 2 h at RT, then was concentratedin vacuo. The residue was partitioned between EtOAc (2.5 mL) and brine(2.5 mL). The organic phase was dried (MgSO₄) and concentrated in vacuo.The crude product was purified by preparative HPLC(YMC reverse phaseODS-A-5 u 30×100 mm column; flow rate=40 mL/min, 10 to 100% solvent Bover 10 min, hold to 13 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA andsolvent B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (23 mg;51%) as a colorless syrup. [M+H]⁺=599.3; ¹H NMR (400 MHz, CDCl₃): δ 1.33(m, 9H), 3.07 (s, 3H), 3.33 (d, 2H), 3.79 (q, 2H), 4.15 (m, 4H), 4.82(m, 1H), 6.93 (s, 1H), 7.05 (d, 1H), 7.15 (d, 2H), 7.44 (s, 1H), 7.70(s, 1H), 7.92 (d, 1H).

Example 47

Powdered KOH (141 mg; 2.51 mmol) was added to a solution of Example 46Part B compound (0.41 g; 1.12 mmol) in DMSO-D6 (2.5 mL). A solution of4-methoxybenzyl bromide (0.47 g; 2.35 mmol) in DMSO-D6 (1 mL) was added.After 2 h H₂O (0.5 mL) was added. After 30 min the solution waspartitioned between EtOAc (20 mL) and H₂O (20 mL). The organic phase wasdried (MgSO₄) and concentrated in vacuo. The crude product waschromatographed (SiO₂; continuous gradient from 0 to 70% EtOAc inhexanes over 13 min, held at 70% EtOAc for 4 min) to give Part Acompound (195 mg; 33%).

Oxalyl chloride (2.0 M in DCM) (72 μL; 0.144 mmol) was added to a 0° C.solution of Part A compound (43.9 mg; 0.096 mmol) in DCM (0.33 mL). DMF(5 μL) was added. Gas evolution occurred. After stirring for 1.5 h at RTthe solution was concentrated in vacuo. The residue was stripped fromCHCl₃ (2 mL). The crude acid chloride was dissolved in DCM (0.40 mL).Example 7 Part B compound (29.4 mg; 0.120 mmol) was added followed bypyridine (23.3 uL; 0.288 mmol). After 14 h at RT the reaction wasconcentrated in vacuo. The residue was partitioned between EtOAc (3 mL)and 0.5 N aqueous HCl (2 mL). The organic phase was washed with sat.aqueous NaHCO₃ (2 mL) and brine (2 mL), dried (MgSO₄) and concentratedin vacuo. The crude product was chromatographed (SiO₂; continuousgradient from 0 to 100% EtOAc in hexanes over 13 min, switched to 3%MeOH in EtOAc and held for 7 min) to give Part B compound (28 mg; 40%).

DDQ (9.4 mg; 0.041 mmol) was added to a solution of Part B compound (28mg; 0.039 mmol) in DCM (400 μL) and H₂O (25 mL). After stirring for 1 hat RT the mixture was concentrated in vacuo. The residue was partitionedbetween EtOAc (3 mL) and sat. aqueous NaHCO₃ (2 mL). The organic phasewas washed with sat. aqueous NaHCO₃ (2 mL) and brine (2 mL), dried(MgSO₄) and concentrated in vacuo. The crude product was purified bypreparative HPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flowrate=40 mL/min, 10 to 100% solvent B over 10 min, hold to 14 min, wheresolvent A=90:10:0.1 H₂O:ACN:TFA and solvent B=90:10:0.1 ACN:H₂O:TFA) togive 20 mg of a syrup. The material was further chromatographed toremove aldehyde contaminant (SiO₂; elute with 100% EtOAc to removealdehyde, then switch to 5% MeOH in EtOAc to elute product) to give thetitle compound (12 mg; 52%) as a colorless syrup. [M+H]⁺=594.3; ¹H NMR(400 MHz, CDCl₃):

1.29 (m, 9H), 2.29 (s, 1H), 3.08 (s, 3H), 3.42 (d, 2H), 3.77 (m, 2H),4.11 (m, 4H), 4.59 (m, 1H), 6.86 (s, 1H), 7.14 (d, 2H), 7.19 (s, 1H),7.37 (s, 1H), 7.93 (d, 2H), 8.30 (s, 1H), 8.68 (s, 1H), 9.57 (s, 1H).

Example 48

NCS (13.1 mg; 0.098 mmol) was added to a solution of Example 13 compound(52.0 mg; 0.098 mmol) in MeOH (0.5 mL) at RT and stirred at RT for 48 h.Volatiles were removed in vacuo. The residue was purified by preparativeHPLC (YMC reverse phase ODS-A-5 u 30×100 mm column; flow rate=40 mL/min,20 to 100% solvent B over 12 min, hold to 18 min, where solventA=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to givethe title compound (42 mg; 76%) as a white solid. [M+H]⁺=563.3; ¹H NMR(400 MHz, CDCl₃): δ 1.13 (m, 2H), 1.29 (m, 6H), 1.48 (m, 2H), 1.60 (m,3H), 1.74 (m, 2H), 1.92 (m, 1H), 2.20 (m, 1H), 3.06 (s, 3H), 3.33 (d,2H), 3.84 (t, 1H), 4.11 (m, 4H), 7.59 (d, 2H), 7.89 (d, 2H).

Example 49

The title compound (23 mg; 69%; white solid) was synthesized employingthe same procedure as for the synthesis of Example 48, except that NBSwas used instead of NCS. The bromination reaction was complete within 1h. [M+H]⁺=607.3; ¹H NMR (400 MHz, CDCl₃):

1.13 (m, 2H), 1.28 (m, 6H), 1.48 (m, 2H), 1.59 (m, 3H), 1.76 (m, 2H),1.92 (m, 1H), 2.20 (m, 1H), 3.06 (s, 3H), 3.31 (d, 2H), 3.83 (t, 1H),4.09 (m, 4H), 7.59 (d, 2H), 7.89 (d, 2H).

Example 50

NCS (8.55 mg; 0.064 mmol) was added to a solution of Example 37 compound(39.0 mg; 0.064 mmol) in MeOH (0.4 mL). After 48 h at RT the reactionmixture was concentrated in vacuo. The crude product was purified bypreparative HPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flowrate=40 mL/min, 25 to 100% solvent B over 10 min, hold to 13 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to give the title compound (27 mg; 66%) as a white solid. [M+H]⁺=647.2;¹H NMR (400 MHz, CDCl₃): δ 1.29 (t, 6H), 1.35 (d, 3H), 3.09 (s, 3H),3.29 (d, 2H), 3.41 (s, 3H), 3.56 (q, 2H), 4.10 (m, 4H), 4.65 (m, 1H),6.89 (s, 1H), 7.15 (d, 2H), 7.19 (s, 1H), 7.36 (s, 1H), 7.94 (d, 2H).

Example 51

The title compound (32 mg; 78%; white solid) was synthesized employingthe same procedure as described for the synthesis of Example 50, exceptthat NBS was used instead of NCS. The bromination reaction was completewithin 1 h. [M+H]⁺=691.3; ¹H NMR (400 MHz, CDCl₃): δ 1.29 (t, 6H), 1.34(d, 3H), 3.09 (s, 3H), 3.33 (d, 2H), 3.41 (s, 3H), 3.55 (q, 2H), 4.09(m, 4H), 4.65 (m, 1H), 6.89 (s, 1H), 7.14 (d, 2H), 7.21 (s, 1H), 7.38(s, 1H), 7.94 (d, 2H).

Example 52

Compound A (120 mg; 16% for 5 steps; soft white solid) was synthesizedfrom methyl 2-amino-5-isopropyl-1,3-thiazole-4-carboxylate employing thesame procedure used to prepare Example 13 Part E compound.

DIPEA (19.2 μL; 0.110 mmol) was added to a solution of Part A compound(33.6 mg; 0.115 mmol), Example 26 Part C compound (36.4 mg; 0.096 mmol)and HOAt (15.0 mg; 0.110 mmol) in DMF (0.35 mL), followed by EDAC (21.1mg; 0.110 mmol). After 24 h at RT the reaction mixture was partitionedbetween EtOAc (15 mL) and 0.5 N aqueous HCl (10 mL). The organic phasewas washed with sat. aqueous NaHCO₃ (10 mL) and brine (10 mL), dried(MgSO₄) and concentrated in vacuo. The crude product was purified bypreparative HPLC(YMC reverse phase ODS-A-5 u 30×100 mm column; flowrate=40 mL/min, 15 to 100% solvent B over 10 min, hold to 12 min, wheresolvent A=90:10:0.1 H₂O:ACN:TFA and solvent B=90:10:0.1 ACN:H₂O:TFA) togive the title compound (49 mg; 75%) as a colorless residue.[M+H]⁺=655.3; ¹H NMR (400 MHz, CDCl₃): δ 1.29 (t, 6H), 1.35 (m, 9H),3.07 (s, 3H), 3.28 (d, 2H), 3.31 (m, 1H), 3.41 (s, 3H), 3.57 (m, 2H),4.13 (m, 4H), 4.84 (m, 1H), 6.92 (s, 1H), 7.15 (d, 2H), 7.38 (s, 1H),7.62 (s, 1H), 7.92 (d, 2H).

Example 53

Diethyl methylphosphonite (690 mg; 5.07 mmol) was added to a solution ofExample 13 Part C compound (496 mg; 1.69 mmol) in THF (0.5 mL). Thereaction mixture was heated at 75° C. for 16 h, then was cooled to RT.The solution was directly loaded onto a 12 g SiO₂ column and the crudeproduct was chromatographed (continuous gradient from 0 to 100% EtOAc inhexanes over 4 min, switched to 5% MeOH in EtOAc and held for 10 min) togive Part A compound (493 mg; 91%) as a light yellow solid.

TFA (2.0 mL) was added to a 0° C. solution of Part A compound (768 mg;2.40 mmol) in DCM (6 mL). The reaction mixture was stirred at RT for 3h, then was concentrated in vacuo. The residue was partitioned betweenEtOAc (15 mL) and sat. aqueous NaHCO₃ (10 mL). The aqueous phase wasextracted with EtOAc (2×10 mL). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo to give Part B compound (203 mg; 38%).

DIPEA (228 μL; 1.31 mmol) was added to a solution of Part B compound(369 mg; 1.67 mmol), Example 26 Part C compound (415 mg; 1.09 mmol) andHOAt (178 mg; 1.31 mmol) in DMF (4.0 mL). EDAC (251 mg; 1.31 mmol) wasadded. After 48 h at RT the reaction mixture was partitioned betweenEtOAc (15 mL) and H₂O (12 mL). The organic phase was washed with 0.5 Naqueous HCl (10 mL), sat. aqueous NaHCO₃ (10 mL) and brine (10 mL),dried (MgSO₄) and concentrated in vacuo. The crude product waschromatographed (SiO₂; continuous gradient from 0 to 100% EtOAc inhexanes over 6 min, switch to 1% MeOH in EtOAc and hold for 4 min, thenswitched to 4% MeOH in EtOAc and hold for 10 min) to give title compound(354 mg; 56%) as a white solid (diastereomeric mixture). [M+H]⁺=583.3;¹H NMR (400 MHz, CDCl₃): δ 1.34 (m, 6H), 1.50 (d, 3H), 3.08 (s, 3H),3.32 (m, 1H), 3.41 (s, 3H), 3.57 (m, 3H), 4.06 (m, 2H), 4.76 (m, 1H),6.89 (s, 2H), 7.15 (d, 2H), 7.44 (s, 1H), 7.61 (s, 1H), 7.92 (d, 2H).

Example 54

The two isomers of Example 53 Part A compound (2.6 g; 8.12 mmol) wereseparated by chiral preparative HPLC (ChiralPak AD, 5×50 cm column, 20μ,isocratic at 15% of 50/50 MeOH:EtOH; 85% heptane, 50 mL/min for 2 h).The material was purified in three runs. Isomer 1 had a retention timeof 38 min and isomer 2 had a retention time of 52 min. Fractionscontaining isomer 1 were concentrated in vacuo to give 1.07 g (82%) of aglassy solid. Fractions containing isomer 2 were concentrated in vacuoto give 1.09 g (84%) of a glassy solid.

HCl (6.0 mL of a 4.0 N solution in 1,4 dioxane) was added to Part Acompound isomer 2 (1.05 g; 3.28 mmol). After stirring at RT for 5 h, thereaction mixture was concentrated in vacuo. The residue was dissolved inH₂O (20 mL), frozen and lyophilized. The lyophilate was dissolved inMeOH (25 mL) and concentrated in vacuo to give Part B compound (0.85 g;100%) as a white foam.

DIPEA (1.45 mL; 8.28 mmol) was added to a solution of Part B compound(0.85 g; 3.31 mmol), Example 26 Part C compound (1.05 g; 2.76 mmol) andHOAt (526 mg; 3.86 mmol) in DMF (10.0 mL). EDAC (741 mg; 3.86 mmol) wasadded. After 72 h at RT the reaction mixture was partitioned betweenEtOAc (140 mL) and H₂O (120 mL). The organic phase was washed with 0.5 Naqueous HCl (100 mL), sat. aqueous NaHCO₃ (100 mL) and brine (80 mL),dried (MgSO₄) and concentrated in vacuo. The crude product was dividedinto 4 portions and purified by preparative HPLC(YMC reverse phaseODS-A-5 u 30×250 mm column; flow rate=30 mL/min, 20 to 100% solvent Bover 20 min, hold to 25 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA andsolvent B=90:10:0.1 MeOH:H₂O:TFA). The product was purified bypreparative HPLC a second time using same conditions but using CH₃CNinstead of MeOH to give the title compound (920 mg; 57%) as a whitesolid. [M+H]⁺=5 83.0; ¹H NMR (400 MHz, CDCl₃): δ 1.33 (m, 6H), 1.45 (d,3H), 3.07 (s, 3H), 3.34 (m, 1H), 3.40 (s, 3H), 3.55 (q, 2H), 3.86 (m,1H), 4.05 (m, 2H), 4.70 (m, 1H), 6.77 (d, 1H), 6.86 (s, 1H), 7.14 (d,2H), 7.49 (s, 1H), 7.62 (s, 1H), 7.91 (d, 2H).

Example 55

The title compound (133 mg, 44% crude yield, white solid) was preparedfrom Example 54 Part A Isomer 1 employing the procedure set forth inExample 54. [M+H]⁺=583.2; ¹H NMR (400 MHz, CDCl₃): δ 1.33 (m, 6H), 1.45(d, 3H), 3.07 (s, 3H), 3.32 (m, 1H), 3.40 (s, 3H), 3.55 (q, 2H), 3.77(m, 1H), 4.06 (m, 2H), 4.70 (m, 1H), 6.77 (d, 1H), 6.86 (s, 1H), 7.14(d, 2H), 7.47 (s, 1H), 7.59 (s, 1H), 7.91 (d, 2H).

Example 56

2.0 N aqueous NaOH (81 μL; 0.162 mmol) was added to a mixture of Example55_compound (31.5 mg; 0.054 mmol) in EtOH (70 μL) and THF (70 μL). After16 h the mixture was partitioned between EtOAc (2 mL) and 0.5 N aqueousHCl (1 mL). The organic phase was washed with brine (1 mL), dried(MgSO₄) and concentrated in vacuo to give title compound (27.4 mg; 91%)as a white solid. [M+H]⁺=555.0; ¹H NMR (400 MHz, CDCl₃): δ 1.28 (d, 3H),1.37 (d, 3H), 3.10 (s, 3H), 3.21 (d, 2H), 3.43 (s, 3H), 3.59 (q, 2H),4.77 (m, 1H), 6.74 (s, 1H), 6.92 (s, 1H), 7.20 (d, 2H), 7.70 (s, 1H),7.77 (s, 1H), 7.93 (d, 2H).

Example 57

2.5 N aqueous NaOH (131 μL; 0.328 mmol) was added to a solution ofExample 37 compound (67 mg; 0.109 mmol) in MeOH (130 μL) and THF (130μL). The solution was heated at 50° C. for 20 h, then was cooled to RTand partitioned between EtOAc (4 mL) and 1.0 N aqueous HCl (2 mL). Theorganic phase was washed with brine (2 mL), dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by preparativeHPLC(YMC reverse phase ODS-A-5 μm 30×100 mm column; flow rate=40 mL/min,15 to 100% solvent B over 10 min, hold to 12 min, where solventA=90:10:0.1 H₂O:ACN:TFA and solvent B=90:10:0.1 ACN:H₂O:TFA) to give awhite solid. The material was purified by preparative HPLC a second time(same conditions as above but using MeOH in place of ACN) to give titlecompound (30 mg; 47%) as a white solid. [M+H]⁺=585.0; ¹H NMR (400 MHz,CD₃OD): δ 1.30 (m, 6H), 3.12 (s, 3H), 3.28 (d, 2H), 3.37 (s, 3H), 3.56(m, 2H), 4.05 (m, 2H), 4.71 (m, 1H), 6.96 (m, 2H), 7.24 (d, 2H), 7.31(s, 1H), 7.48 (s, 1H), 7.97 (d, 2H).

Examples 58 and 59

To a stirred 0° C. solution of 5-methyl-1H-pyrazol-3-amine (260 mg, 2.68mmol) in DMF (4 mL) was added KOtBu (601 mg, 5.35 mmol). The reactionwas stirred at 0° C. for 30 min, and then ICH₂PO₃Et₂ (1116 mg, 4.02mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h,then was warmed to RT and stirred at RT for 18 h. Volatiles were removedin vacuo at 50° C. The residue was partitioned between EtOAc and brine.The aqueous layer was extracted with EtOAc (4×), and the combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo to give abrown oil. The crude residue was purified by preparative HPLC (Luna 5 u21.2×100 mm column; flow rate=20 mL/min, 0 to 100% solvent B over 12min, hold to 15 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA) to afford the Part A compounds (1:1 mixture,80 mg, 12%) as a white solid.

To a RT solution of Example 26C acid (0.110 g, 0.288 mmol) in DMF (4.5mL), was added EDC (0.110 g, 0.576 mmol), HOAT (0.078 g, 0.576 mmol),and DIEA (0.088 mL, 0.5004 mmol). The homogeneous yellow solution wasstirred at 25° C. for 30 min. A solution of Part A compound (0.100 g,288 mmol) in DIEA (0.088 mL, 0.5004 mmol) and DMF (1.5 mL) was added,and the homogeneous yellow reaction mixture was stirred at 25° C. for 2h, then was poured into water (15 mL). The mixture was extracted withEtOAc (10 mL); the organic phase was dried (MgSO₄) and concentrated invacuo. The residue was purified by preparative HPLC (Phenomenex Luna 5μC18 30×250 mm column; detection at 220 nm; flow rate=20 mL/min.;continuous gradient from 100% A to 100% B over 30 min.+7 min. hold at100% B, where A=90:10 H₂O:MeOH and B=90:10 MeOH:H₂O) to provide a yellowfoam (a mixture of the two regioismers).

The regioisomers were separated by chiral preparative HPLC (5 cm×50 cmAD column, detection at 220 nm, isocratic 50:50 EtOH:MeOH mobile phase,50 mL/min. flow) to provide the title compound 58 (27 mg, 15.2% yield)as a tan solid and the title compound 59 (64 mg, 36.3% yield) as anoff-white solid.

Example 58

[M+H]⁺=610.4; ¹H NMR (400 MHz, CDCl₃)

10.56 (s, 1H), 7.91 (d, J=8.79 Hz, 2H), 7.52 (t, J=1.75, 1.76 Hz, 1H),7.37 (t, J=1.75, 1.32 Hz, 1H), 7.15 (d, J=8.79 Hz, 2H), 6.83 (t, J=2.20Hz, 1H), 6.44 (s, 1H), 4.64-4.74 (m, 1H), 4.50 (d, J=10.55 Hz, 2H),3.97-4.17 (m, 4H), 3.49-3.64 (m, 2H), 3.42 (s, 3H), 3.07 (s, 3H), 2.26(s, 3H), 1.36 (d, J=6.15 Hz, 3H), 1.27 (t, J=7.03 Hz, 6H).

Example 59

[M+H]⁺=610.4; ¹H NMR (400 MHz, CDCl₃)

8.6 (s, 1H), 7.92 (d, J=8.79 Hz, 2H), 7.31 (t, J=1.76 Hz, 1H), 7.12-7.17(m, 3H), 6.83 (t, J=2.19, 1.76 Hz, 1H), 6.66 (s, 1H), 4.57-4.69 (m, 1H),4.37 (d, J=11.42 Hz, 2H), 4.01-4.15 (m, 4H), 3.48-3.63 (m, 2H), 3.42 (s,3H), 3.09 (s, 3H), 2.34 (s, 3H), 1.34 (d, J=6.59 Hz, 3H), 1.29 (t,J=7.03 Hz, 6H).

Example 60

To a suspension of 3-nitro-1H-pyrazole (1.00 g, 8.84 mmol) in water (31mL) was added formaldehyde (37 wt % in water, 1.317 mL, 17.69 mmol). Thereaction mixture was stirred at RT for 48 h (after 2 h the reactionmixture became a homogeneous pale yellow solution). The reaction mixturewas diluted with sat. aqueous NaHCO₃ (20 mL) and extracted with CH₂Cl₂(4×40 mL) and EtOAc (3×50 mL). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo to provide Part A compound (1.26 g,99% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD)

7.69 (d, J=2.20 Hz, 1H), 6.95 (d, J=2.75 Hz, 1H), 5.62 (d, J=7.70 Hz,2H), 4.40 (t, J=7.70, 7.69 Hz, 1H).

To a 75° C. solution of Part A compound (1.809 g, 12.64 mmol) in MeCN(54 mL) was added PBr₃ (1.788 mL, 18.96 mmol) dropwise over 10 min. Thereaction mixture was stirred at 75° C. for 15 min, then was cooled to RTand filtered. The filter cake was washed with CH₃CN (2×2 mL), and thecombined filtrates were concentrated in vacuo. The residue waspartitioned between EtOAc (50 mL) and sat. aqueous NaHCO₃ (30 mL). Theorganic phase was washed with brine (20 mL), dried (MgSO₄), andconcentrated in-vacuo. The residue was chromatographed (SiO₂: continuousgradient 0% EtOAc/Hexane to 70% EtOAc/Hex) to provide Part B compound(1.693 g, 65% yield) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃)

7.80 (d, J=2.20 Hz, 1H), 7.01 (d, J=2.75 Hz, 1H), 5.98 (s, 2H).

To a solution of Part B compound (1.7366 g, 8.43 mmol) in THF (4 mL) wasadded CH₃P(OEt)₂ (1.377 g, 10.12 mmol). The reaction mixture was stirredat 75° C. for 15 h. Additional CH₃P(OEt)₂ (0.53 g, 3.89 mmol) was added,and the reaction mixture was stirred at 75° C. for 24 h, then was cooledto RT. Volatiles were removed in vacuo, and the residue waschromatographed (SiO₂: continuous gradient from 0% MeOH/CH₂Cl₂ to 15%MeOH/CH₂Cl₂) to provide Part C compound (1.56 g, 80% yield) as an orangeoil. [M+H]⁺=234.1; ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=3.30 Hz, 1H),6.96 (d, J=2.75 Hz, 1H), 4.63 (d, J=9.34 Hz, 2H), 4.03-4.20 (m, 4H),1.57 (d, J=14.85 Hz, 3H), 1.30-1.37 (m, 6H).

To a solution of Part C compound (1.60 g, 6.86 mmol) in MeOH (190 mL)was added 10% Pd/C (0.730 g, 0.686 mmol). The reaction mixture wasstirred under an H₂(g) atmosphere for 3 h. The reaction mixture wasfiltered through Celite®, and the filtrate was concentrated in vacuo.The individual stereoisomers were separated on a Chiralcel OJ column (5cm×50 cm, isocratic conditions: 40% IPA in heptane, detection at 220 nm,50 mL/min. flow) to provide isomer D1 (0.59 g, 42.3% yield) as anoff-white solid and isomer D2 (0.56 g, 40% yield) as a tan solid.

Isomer D1: [M+H]⁺=204.1; ¹H NMR (400 MHz, CDCl₃)

7.24 (d, J=2.19 Hz, 1H), 5.66 (d, J=2.20 Hz, 1H), 4.32 (d, J=8.79 Hz,2H), 4.02-4.17 (m, 2H), 3.59-3.81 (s, 2H), 1.48 (d, J=14.50 Hz, 3H),1.33 (t, J=7.03 Hz, 3H), specific rotation=48.5°.

Isomer D2: [M+H]⁺=204.1; ¹H NMR (400 MHz, CDCl₃)

7.21-7.27 (m, 1H), 5.62-5.70 (m, 1H), 4.32 (d, J=8.79 Hz, 2H), 4.01-4.19(m, 2H), 3.55-3.81 (s, 2H), 1.48 (d, J=14.50 Hz, 3H), 1.33 (t, J=7.03Hz, 3H), specific rotation=−49.6°.

To a RT solution of Example 26 Part C compound (0.120 g, 0.315 mmol) inDMF (6 mL) was added EDAC (0.121 g, 0.631 mmol), HOAT (0.086 g, 0.631mmol), and DIEA (0.165 mL, 0.946 mmol). The reaction mixture was stirredat RT for 30 min and Part D1 compound (0.064 g, 0.315 mmol) was added.The reaction mixture was stirred at RT for 18 h. The reaction mixturewas poured into water (40 mL) and the mixture was extracted with EtOAc(3×15 mL). The combined organic extracts were concentrated in vacuo. Theresidue was purified by preparative HPLC (Phenomenex Luna 5 μm. C1830×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuousgradient from 100% A to 100% B over 20 min.+2 min. hold at 100% B, whereA=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH: H₂O:TFA) to provide thetitle compound (0.121 g, 68.1% yield) as a white solid. [M+H]⁺=566.3; ¹HNMR (400 MHz, CDCl₃):

9.24 (s, 1H), 7.91 (d, J=8.78 Hz 2H), 7.46 (d, J=1.76 Hz, 1H), 7.38 (t,J=1.76 Hz, 1H), 7.23 (t, J=1.76 Hz, 1H), 7.13 (d, J=8.79 Hz, 2H), 6.96(d, J=2.19 Hz, 1H), 6.84 (t, J=2.20 Hz, 1H), 4.73-4.63 (m, 1H), 4.56(dd, J=16.25, 8.35 Hz, 1H), 4.46 (dd, J=15.82, 8.35, 9.67 Hz, 1H),4.20-4.05 (m, 2H), 3.63-3.50 (m, 2H), 3.42 (s, 3H), 3.08 (s, 3H), 1.51(d, J=14.5 Hz, 3H), 1.39-1.29 (m, 6H).

Example 61

To a RT solution of Example 26C acid (0.120 g, 0.315 mmol) in DMF (6 mL)was added EDAC (0.121 g, 0.631 mmol), HOAT (0.086 g, 0.631 mmol), andDIEA (0.165 mL, 0.946 mmol). The reaction mixture was stirred at RT for30 min and Example 60 Part D2 compound (0.064 g, 0.315 mmol) was added.The reaction mixture was stirred at RT for 18 h, then was poured intowater (40 mL). The mixture was extracted with EtOAc (3×15 mL); thecombined organic extracts were concentrated in vacuo. The residue waspurified by preparative HPLC (Phenomenex Luna 5 μm. C18 30×100 mmcolumn; detection at 220 nm; flow rate=40 mL/min.; continuous gradientfrom 100% A to 100% B over 20 min.+2 min. hold at 100% B, whereA=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH: H₂O:TFA) to provide thetitle compound (0.117 g, 65.4% yield) as a white solid. [M+H]⁺=566.3; ¹HNMR (400 MHz, CDCl₃): δ 9.19 (s, 1H), 7.92 (d, J=9.22 Hz 2H), 7.46 (d,J=1.76 Hz, 1H), 7.37 (t, J=1.76 Hz, 1H), 7.22 (t, J=1.76 Hz, 1H), 7.13(d, J=8.78 Hz, 2H), 6.96 (d, J=2.63 Hz, 1H), 6.85 (t, J=2.20 Hz, 1H),4.72-4.62 (m, 1H), 4.56 (dd, J=16.25, 8.35 Hz, 1H), 4.46 (dd, J=15.82,8.35, 9.67 Hz, 1H), 4.19-4.05 (m, 2H), 3.63-3.50 (m, 2H), 3.42 (s, 3H),3.08 (s, 3H), 1.51 (d, J=14.5 Hz, 3H), 1.38-1.29 (m, 6H).

Example 62

To a RT solution of Example 33 Part A acid ((0.030 g, 0.087 mmol) in DMF(2.0 mL) was added EDAC (0.033 g, 0.174 mmol), HOAt (0.024 g, 0.174mmol) and DIEA (0.046 mL, 0.261 mmol). The reaction mixture was stirredat RT for 30 min, after which Example 60 Part D1 compound (0.018 g,0.087 mmol) was added. The reaction mixture was stirred at RT for 18 h,then was poured into water (20 mL). The mixture was extracted with EtOAc(2×10 mL); the combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex Luna 5μ, C18 21.2×100 mm column; detection at 220 nm; flowrate=40 mL/min.; continuous gradient from 100% A to 100% B over 15min.+2 min. hold at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH: H₂O:TFA) to provide the title compound (0.034 g, g,74.8% yield) as a tacky off-white solid. [M+H]⁺=530.4; ¹H NMR (400 MHz,CDCl₃): δ 9.16 (s, 1H), 7.45 (d, J=1.65 Hz, 1H), 7.32-7.18 (m, 5H), 7.06(t, J=1.65 Hz, 1H), 7.03 (t, J=1.65 Hz, 1H), 6.98 (d, J=2.19 Hz, 1H),6.64 (t, J=2.2 Hz, 1H), 4.69-4.56 (m, 2H), 4.55-4.40 (m, 2H), 4.18-4.04(m, 2H), 3.57 (dd, J=10.45 Hz, J=6.04 Hz, 1H), 3.50 (dd, J=9.89 Hz,J=3.85 Hz, 1H), 3.41 (s, 3H), 3.06 (dd, J=13.74 Hz, J=6.04 Hz, 1H), 2.86(dd, J=13.75 Hz, J=6.05 Hz, 1H), 1.53 (d, J=14.84 Hz, 3H), 1.35-1.27 (m,9H).

Example 63

To a RT solution of Example 33 Part A acid ((0.030 g, 0.087 mmol) in DMF(2.0 mL) was added EDAC (0.033 g, 0.174 mmol), HOAt (0.024 g, 0.174mmol) and DIEA (0.046 mL, 0.261 mmol). The reaction mixture was stirredat RT for 30 min, after which Example 60 Part D2 compound (0.018 g,0.087 mmol) was added. The reaction was stirred at RT for 18 h, then waspoured into water (20 mL). The mixture was extracted with EtOAc (2×10mL) and the combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex Luna 5μ, C18 21.2×100 mm column; detection at 220 nm; flowrate=40 mL/min.; continuous gradient from 100% A to 100% B over 15min.+2 min. hold at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH: H₂O:TFA) to provide the title compound (0.03626 g, 79%yield) as a tacky white solid. [M+H]⁺=530.4; ¹H NMR (400 MHz, CDCl₃): δ9.17 (s, 1H), 7.45 (d, J=2.20 Hz, 1H), 7.32-7.17 (m, 5H), 7.06 (t, J=2.2Hz, 1H), 7.03 (t, J=2.2 Hz, 1H), 6.98 (d, J=2.19 Hz, 1H), 6.64 (t, J=2.2Hz, 1H), 4.70-4.57 (m, 2H), 4.54-4.40 (m, 2H), 4.17-4.03 (m, 2H), 3.57(dd, J=9.90 Hz, J=6.04 Hz, 1H), 3.50 (dd, J=10.44 Hz, J=3.38 Hz, 1H),3.41 (s, 3H), 3.06 (dd, J=13.74 Hz, J=6.59 Hz, 1H), 2.85 (dd, J=13.75Hz, J=6.05 Hz, 1H), 1.52 (d, J=14.29 Hz, 3H), 1.36-1.26 (m, 9H).

Example 64

A mixture of methyl 3,5-dihydroxybenzoate (350 mg, 2.082 mmol),5-(chloromethyl) oxazolidin-2-one (1.0 g, 7.38 mmol), and K₂CO₃ (5.75 g,41.6 mmol) in DMF (10 mL) was stirred at 80° C. for 18 h, then wascooled to RT and filtered. The filter cake was washed with EtOAc, andthe combined filtrates were concentrated in vacuo to give a brown oil.The crude methyl bis-alkylated benzoate was dissolved in THF (1 mL), andaqueous 1N NaOH (1 mL, 1.00 mmol) was added. The mixture was stirred atRT for 18 h, then concentrated in vacuo. The residue was acidified withTFA and then purified by preparative HPLC (Phenomenex AXIA 5 u C1830×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuousgradient from 30% A to 100% B over 10 min+1 min hold time at 100% B,where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to givePart A compound (83 mg, 9% yield) as a red solid. [M+H]⁺=353.1; ¹H NMR(400 MHz, MeOH-d₄) δ 3.56 (dd, J=8.79, 6.60 Hz, 2H) 3.75 (t, J=9.07 Hz,2H) 4.10-4.30 (m, 4H) 4.96-5.07 (m, 2H) 6.77-6.85 (m, 0H) 7.22 (d,J=2.75 Hz, 2H).

A mixture of Part A compound (13 mg, 0.037 mmol), Example 13 Part Ecompound (23 mg, 0.037 mmol), HOAt (10 mg, 0.072 mmol), EDCI (20 mg,0.500 mmol) and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL) was stirredat 21° C. for 18 h. The reaction mixture was diluted with EtOAc (1 mL)and washed with 1N aqueous HCl (1 mL). The organic layer was dried(MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex AXIA 5 u C18 30×100 mm column; detection at220 nm; flow rate=40 mL/min; continuous gradient from 30% A to 100% Bover 10 min+1 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (12.5 mg, 58.0%yield) as a white solid. [M+H]⁺=585.3; ¹H NMR (400 MHz, CDCl₃) δ 1.33(t, J=7.15 Hz, 6H) 3.35 (d, J=21.44 Hz, 2H) 3.63 (dd, J=8.25, 6.60 Hz,2H) 3.79 (t, J=8.79 Hz, 2H) 4.11-4.20 (m, 4H) 4.21-4.37 (m, 4 H)4.96-5.04 (m, 2H) 5.76 (br. s., 2H) 6.80 (br. s., 1H) 7.04 (d, J=3.85Hz, 1H) 7.44 (s, 2H).

Example 65

A suspension of NaH (70 mg of a 60% suspension in oil, 1.750 mmol) inTHF (3 mL) was stirred at 0° C. under N₂ (g) for 15 min. The reactionwas cooled to −30° C. and oxazolidin-2-one (125 mg, 1.436 mmol) wasadded. The mixture was stirred at −30° C. for 30 min, then was warmed toRT and stirred for 30 min. The mixture was cooled to −30° C. again and asolution of methyl 3-(bromomethyl)-5-methoxybenzoate (200 mg, 0.772mmol) in THF (2 mL) was added. The mixture was stirred at RT for 5 days,then was cooled to −30° C. and sat. aqueous NH₄Cl (1 mL) was added. Theaqueous layer was back-extracted with EtOAc (2×5 mL), and the combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Theresidue was chromatographed [SiO₂; EtOAc/Hexane (1:1)] to give Part Acompound 184 mg, 90% yield) as a clear oil. [M+H]⁺=266.01; ¹H NMR (500MHz, CDCl₃) δ 3.46 (t, J=7.70 Hz, 2H) 3.85 (s, 3H) 3.92 (s, 3H) 4.33 (t,J=7.70 Hz, 2H) 4.44 (s, 2 H) 7.05 (s, 1H) 7.50 (s, 1H) 7.54 (s, 1H).

A mixture of Part A compound (50 mg, 0.188 mmol), and NaOH (1 mL, 1.00mmol) in THF (2 mL) was stirred at RT for 2 h, then was acidified with1N aqueous HCl (0.5 mL). The mixture was filtered and concentrated invacuo; the residue was purified by preparative HPLC (Phenomenex AXIA 5 uC18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 30% A to 100% B over 10 min+1 min hold time at100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) togive Part B compound as a white solid (42 mg, 0.167 mmol, 89%).[M+H]⁺=251.98; ¹H NMR (400 MHz, CD₃OD) δ 3.53 (t, J=8.24 Hz, 2H), 3.84(s, 3H), 4.34 (t, J=8.24 Hz, 2H), 4.44 (s, 2 H), 7.09 (t, J=1.65 Hz,1H), 7.49 (dd, J=2.75, 1.10 Hz, 1H), 7.55 (s, 1H).

A mixture of Part B compound (12 mg, 0.048 mmol), Example 13 Part Ecompound (11.95 mg, 0.048 mmol), HOAt (10 mg, 0.072 mmol), DIPEA (0.2mL, 1.148 mmol) and EDCI (20 mg, 0.500 mmol) in DMF (0.5 mL) was stirredat RT in for 18 h, then was diluted with EtOAc (1 mL) and washed with 1Naqueous HCl (1 mL). Volatiles were removed in vacuo. The crude residuewas purified by preparative HPLC (Phenomenex AXIA 5 u C18 30×100 mmcolumn; detection at 220 nm; flow rate=40 mL/min; continuous gradientfrom 30% A to 100% B over 10 min+1 min hold time at 100% B, whereA=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give the titlecompound as a clear oil (20 mg, 87% yield). [M+H]⁺=483.99; ¹H NMR (400MHz, CDCl₃) δ 1.33 (t, J=7.15 Hz, 6H), 3.36 (d, J=21.44 Hz, 2H), 3.52(s, J=8.24, 8.24 Hz, 2H), 3.91 (s, 3H), 4.12-4.22 (m, J=7.35, 7.35,7.28, 7.15 Hz, 4H) 4.33 (t, J=8.25 Hz, 2H), 4.46 (s, 2H), 7.05 (d,J=3.30 Hz, 1H), 7.17 (s, 1H), 7.66 (s, 1H), 7.68 (d, J=2.20 Hz, 1H).

Example 66

To a 0° C. solution of Example 64 Part B compound (177 mg, 0.667 mmol)in DCM (1 mL) was added BBr₃ (1 mL, 1.000 mmol). The reaction wasstirred at 0° C. for 24 h, after which volatiles were removed in vacuo.The residue was dissolved in MeOH (3 mL), and the pH was adjusted topH-4 with sat. aqueous NaHCO₃. Solids were removed by filtration, andthe filtrate was concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex AXIA 5 u C18 30×100 mm column; detection at220 nm; flow rate=40 mL/min; continuous gradient from 30% A to 100% Bover 10 min+1 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to give the Part A compound (67 mg, 40%yield) as a white solid. [M+H]⁺=252.19; ¹H NMR (400 MHz, CD₃OD) δ 3.52(t, J=8.24 Hz, 2H), 3.88 (s, 3H), 4.34 (t, J=8.24 Hz, 2H), 4.40 (s, 2H), 6.97 (s, 1H), 7.36 (s, 1H), 7.42 (s, 1H).

A solution of Part A compound (67 mg, 0.267 mmol),1-fluoro-4-(methylsulfonyl)benzene (50 mg, 0.287 mmol), and K₂CO₃ (300mg, 2.171 mmol) in DMF (3 mL) was stirred at 100° C. in a sealed tubefor 18 h, then was cooled to RT. Solids were filtered off, and thefiltrate was concentrated in vacuo. The residue was acidified with TFAand then purified by preparative HPLC (Phenomenex AXIA 5 μm C18 30×100mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradientfrom 30% A to 100% B over 10 min+1 min hold time at 100% B, whereA=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give Part Bcompound (73 mg, 69.9% yield) as a white solid. [M+H]⁺=392.01; ¹H NMR(400 MHz, CD₃OD) δ 3.12 (s, 3H), 3.57 (t, J=8.24 Hz, 2H), 4.36 (t,J=8.24 Hz, 2H), 4.50 (s, 2H), 7.20 (d, J=8.79 Hz, 2H), 7.32 (s, 1H),7.63 (s, 1H), 7.84 (s, 1H), 7.96 (d, J=8.79 Hz, 2H).

A mixture of Part B compound (15 mg, 0.038 mmol), Example 13 Part Ecompound (9.59 mg, 0.038 mmol), HOAt (10 mg, 0.072 mmol), EDCI (20 mg,0.500 mmol), and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL) was stirredat 25° C. for 18 h. The mixture was diluted with EtOAc (1 mL) and washedwith 1N aqueous HCl (1 mL). The organic phase was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex AXIA 5 u C18 30×100 mm column; detection at 220 nm; flowrate=40 mL/min; continuous gradient from 30% A to 100% B over 10 min+1min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (17 mg, 70% yield) as a whitesolid. [M+H]⁺=624.2; ¹H NMR (400 MHz, CDCl₃) (1.32 (t, J=7.15 Hz, 6H),3.07 (s, 3H), 3.33 (d, J=21.44 Hz, 2H), 3.64 (t, J=7.70 Hz, 2H), 4.15(dd, J=8.25, 7.15 Hz, 4H), 4.35 (t, J=8.24 Hz, 2H), 4.51 (s, 2H), 7.05(d, J=3.85 Hz, 1H), 7.14 (d, J=8.79 Hz, 2H), 7.40 (s, 1H), 7.76 (t,J=1.65 Hz, 1H), 7.89-7.96 (m, 3H).

Example 67

A mixture of methyl 3,5-dihydroxybenzoate (10 g, 59.5 mmol) and K₂CO₃(13 g, 94 mmol) in DMF (50 mL) was stirred at 120° C. for 2 h. Asolution of 1-fluoro-4-(methylsulfonyl)benzene (5 g, 28.7 mmol) in DMF(10 mL) was added, and the reaction was stirred at 120° C. for another24 h. The reaction mixture was filtered, and the resulting filter cakewas rinsed with DMF (50 mL). The combined filtrates were concentrated invacuo. The residue was partitioned between EtOAc (100 mL) and 1N aqueousHCl (100 mL). The aqueous layer was extracted with EtOAc (50 mL×3), andthe combined organic extracts were washed with water, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude residue waschromatographed (SiO₂; EtOAc/Hexane 1:3) to give Part A compound (4 g,43% yield) as yellow solid. [M+H]⁺=323.0; ¹H NMR (400 MHz, CDCl₃)

3.08 (s, 3H), 3.91 (s, 3H), 6.13 (s, 1H), 6.80 (t, J=2.20 Hz, 1H), 7.11(d, J=8.79 Hz, 2H), 7.27-7.28 (m, 1H), 7.41-7.44 (m, 1H), 7.91 (d,J=8.79 Hz, 2H).

To a stirred solution of 5-(chloromethyl)-2H-tetrazole (0.5 g, 4.22mmol) in Et₂O (5 mL) was added dropwise a solution of CH₂N₂ in Et₂O (5mL) prepared from 1-methyl-3-nitro-1-nitrosoguanidine (700 mg, 4.76mmol) and 40% aqueous KOH (4 g, 28.5 mmol, 10 mL water) at 0° C. Thereaction solution was maintained at 0° C. during the addition, and thereaction was stirred at RT for 1 h and was then concentrated using astream of air. Residual solvent was removed in vacuo to give the Part βisomeric compounds as yellow oils (400 mg, 71.5% yield).

A mixture of Part A compound (100 mg, 0.310 mmol), Part B compound (41.1mg, 0.310 mmol), and K₂CO₃ (300 mg, 2.17 mmol) was stirred at 100° C. ina sealed tube for 18 h, then was cooled to RT. The reaction mixture wasdiluted with EtOAc (5 mL) and washed with H₂O (5 mL×2); the organiclayer was dried (Na₂SO₄) and concentrated in vacuo to give a yellow oil.This crude methyl ester was stirred in 1N aqueous NaOH (0.5 mL, 0.500mmol) and THF (1 mL) for 2 h. The reaction was concentrated in vacuo andwas acidified with TFA. The two isomers were separated by preparativeHPLC (Phenomenex AXIA 5 u C18 30×100 mm column; detection at 220 nm;flow rate=40 mL/min; continuous gradient from 30% A to 100% B over 10min+1 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to give Part Cl compound (40 mg, 31% yield) asa white solid and Part C2 compound (72 mg, 57% yield) as a white solid.

Part C1-Compound: [M+H]⁺=405.1; ¹H NMR (400 MHz, DMSO-d6) δ 3.22 (s,3H), 4.13 (s, 3H), 5.63 (s, 2H), 7.20-7.28 (m, 4H), 7.49 (s, 1H), 7.95(d, J=8.79 Hz, 2H), 13.35 (s, 1H).

Part C2 Compound: [M+H]⁺=405.1; ¹H NMR (400 MHz, DMSO-d6) δ 3.21 (s,3H), 4.38 (s, 3H), 5.47 (s, 2H), 7.18 (d, J=5.50 Hz, 2H), 7.24 (d,J=8.79 Hz, 2H), 7.44 (s, 1H), 7.94 (d, J=8.79 Hz, 2H), 13.30 (s, 1H).

A mixture of Part Cl compound (12 mg, 0.030 mmol), Example 13 Part Ecompound (7.43 mg, 0.030 mmol), HOAt (10 mg, 0.072 mmol), EDCI (20 mg,0.500 mmol), and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL) was stirredat 25° C. for 18 h. The reaction mixture was diluted with EtOAc (1 mL)and washed with 1N aqueous HCl (1 mL). The organic layer was dried(Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex AXIA 5 μm C18 30×100 mm column; detectionat 220 nm; flow rate=40 mL/min; continuous gradient from 30% A to 100% Bover 10 min+1 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (12 mg, 64%yield) as a white solid. [M+H]⁺=636.99; ¹H NMR (400 MHz, CDCl₃) δ 1.30(t, J=6.87 Hz, 6H), 3.08 (s, 3H), 3.29 (d, J=21.44 Hz, 2H), 4.08-4.17(m, J=7.56, 7.56, 7.42, 7.15 Hz, 4H), 4.18 (s, 3H), 5.56 (s, 2H), 6.98(s, 1H), 7.03 (d, J=3.30 Hz, 1H), 7.15 (d, J=8.79 Hz, 2H), 7.50 (s, 1H),7.80 (s, 1H), 7.94 (d, J=8.79 Hz, 2H).

Example 68

A mixture of Example 67 Part C2 Compound (12 mg, 0.030 mmol), Example 13Part E compound (7.43 mg, 0.030 mmol), HOAt (10 mg, 0.072 mmol), DIPEA(0.2 mL, 1.148 mmol), and EDCI (0.500 mL, 0.500 mmol) in DMF (0.5 mL)was stirred at 25° C. for 18 h. The reaction mixture was diluted withEtOAc (1 mL) and washed with 1N aqueous HCl (1 mL). The organic layerwas dried (Na₂SO₄) and concentrated in vacuo. The residue was purifiedby preparative HPLC (Phenomenex AXIA 5 μm C18 30×100 mm column;detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% Ato 100% B over 10 min+1 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound(10 mg, 53% yield) as a white solid. [M+H]⁺=637.00; ¹H NMR (400 MHz,CDCl₃) δ 1.30 (t, J=7.15 Hz, 6H), 3.07 (s, 3H), 3.32 (d, J=21.44 Hz,2H), 4.07-4.17 (m, J=7.35, 7.35, 7.28, 7.15 Hz, 4H), 4.39 (s, 3H), 5.48(s, 2 H), 6.97-7.02 (m, 2H), 7.15 (d, J=8.79 Hz, 2H), 7.49 (s, 1H), 7.78(s, 1H), 7.93 (d, J=8.79 Hz, 2H).

Example 69

A mixture of 1-(bromomethyl)-4-methoxybenzene (2.151 mL, 14.92 mmol),methyl 3,5-dihydroxybenzoate (5 g, 29.7 mmol), and K₂CO₃ (12.33 g, 89mmol) in MeCN (100 mL) was stirred at 80° C. for 3 days. The reactionwas diluted with water (50 mL), acidified with 12N HCl (30 mL) to pH-2,and extracted with EtOAc (20 mL×3). The combined organic extracts werewashed with water, dried (Na₂SO₄) and concentrated in vacuo. The residuewas chromatographed (SiO₂: EtOAc/Hexane 1:3) to give Part A compound(3.0 g, 35% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 3.82 (s,3H), 3.90 (s, 3H), 5.00 (s, 2H), 5.14 (s, 1H), 6.66 (t, J=2.20 Hz, 1H),6.92 (d, J=8.35 Hz, 2H), 7.10-7.16 (m, 1H), 7.22-7.29 (m, 1H), 7.35 (d,J=8.35 Hz, 2H).

To a 0° C. solution of Ph₃P (1.820 g, 6.94 mmol), Part A compound (1 g,3.47 mmol), and (R)-1-methoxypropan-2-ol (0.365 mL, 4.16 mmol) in dryTHF (5 mL) was added DIAD (1.012 mL, 5.20 mmol). The reaction wasstirred at RT for 18 h. Volatiles were removed in vacuo, and the residuewas chromatographed (SiO₂; EtOAc/Hexane, 1:5) to give crude Part Bcompound (1.7 g, 136%), which was used in the next step without furtherpurification.

A solution of crude Part B compound (1.75 g, 4.86 mmol) and TFA (3 mL,38.9 mmol) in dry DCM (5 mL) was stirred at RT for 2 h. Volatiles wereremoved in vacuo, and the residue was chromatographed (SiO₂;EtOAc/Hexane 1:5) to give Part C compound (407 mg, 35%) as a clear oil.[M+H]⁺=241.27; ¹H NMR (400 MHz, CDCl₃) δ 1.29 (d, J=6.05 Hz, 3H), 3.41(s, 3H), 3.47-3.62 (m, 2H), 3.88 (s, 3H), 4.51-4.62 (m, 1H), 4.95 (br.s., 1H), 6.65 (s, 1H), 7.13 (dd, J=5.22, 1.37 Hz, 2H).

A mixture of Part C compound (300 mg, 1.249 mmol), Example 67 Part Bcompound (166 mg, 1.249 mmol), and K₂CO₃ (300 mg, 2.171 mmol) in DMF (3mL) was stirred at 100° C. in a sealed tube for 18 h, then was cooled toRT. Solids were filtered off, and the filtrate was concentrated invacuo. The residue was acidified with TFA and the two isomers wereseparated by preparative HPLC (Phenomenex AXIA 5 u C18 30×100 mm column;detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% Ato 100% B over 10 min+1 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give Part D1 compound (160mg, 40% yield) as a white solid and Part D2 compound (33 mg, 8.2% yield)as a white solid.

Part D1 compound: [M+H]⁺=323.15; ¹H NMR (400 MHz, CDCl₃) δ 1.31 (d,J=6.05 Hz, 3H), 3.43 (s, 3H), 3.50-3.64 (m, 2H), 4.18 (s, 3H), 4.57-4.67(m, 1H), 5.47 (s, 2H), 6.82 (t, J=2.47 Hz, 1H), 7.30 (dd, J=2.20, 1.10Hz, 1H), 7.35 (s, 1H).

Part D2 compound: [M+H]⁺=323.18; ¹H NMR (400 MHz, CDCl₃) δ 1.32 (d,J=6.05 Hz, 3H), 3.42 (s, 3H), 3.48-3.62 (m, 2H), 4.39 (s, 3H), 4.55-4.64(m, 1H), 5.35 (s, 2H), 6.86 (t, J=2.47 Hz, 1H), 7.34 (s, 1H), 7.37 (dd,J=2.20, 1.10 Hz, 1H).

A mixture of Part D1 compound (15 mg, 0.047 mmol), Example 13 Part Ecompound (11.65 mg, 0.047 mmol), HOAt (10 mg, 0.072 mmol), EDCI (20 mg,0.500 mmol), and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL) was stirredat 25° C. for 18 h. The reaction mixture was diluted with EtOAc (1 mL)and washed with 1N aqueous HCl (1 mL). The organic phase was dried(Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC(Phenomenex AXIA 5 u C18 30×100 mm column; detection at220 nm; flow rate=40 mL/min; continuous gradient from 30% A to 100% Bover 10 min+1 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (13 mg, 50%yield) as a white solid. [M+H]⁺=555.3; ¹H NMR (400 MHz, CDCl₃) δ1.28-1.35 (m, 9H), 3.29-3.36 (m, 2H), 3.40 (s, 3H), 3.49-3.61 (m, 2H),4.09-4.19 (m, 7H), 4.74 (td, J=6.19, 3.79 Hz, 1H), 5.49 (s, 2H), 6.84(t, J=2.15 Hz, 1H), 7.03 (d, J=3.54 Hz, 1H), 7.47 (t, J=1.77 Hz, 1H),7.49 (dd, J=2.02, 1.52 Hz, 1H).

Example 70

The title compound (10 mg; 58% yield; colorless oil) was synthesizedemploying the procedure described in Example 69 Part E, except thatExample 69 Part D2 was used in the sequence instead of Example 69 PartD1. [M+H]⁺=555.3; ¹H NMR (400 MHz, CDCl₃) δ 1.25-1.37 (m, 9H), 3.26-3.37(m, 2H), 3.40 (s, 3H), 3.47-3.62 (m, 2H), 4.06-4.19 (m, 4H), 4.38 (s,3H), 4.71 (td, J=6.19, 4.04 Hz, 1H), 5.40 (s, 2H), 6.86 (t, J=2.27 Hz,1H), 6.98 (d, J=3.54 Hz, 1H), 7.40 (d, J=1.52 Hz, 1H), 7.45 (d, J=1.52Hz, 1H).

Example 71

To a solution of FeCl₃ (100 mg, 0.62 mmol) in HOAc (68.8 mL, 1202 mmol)was added 2-(chloromethyl)oxirane (111.2 g, 1202 mmol) with stirring,over a 10-min period. The mixture was heated at 70° C. with stirring for24 h, then was cooled to RT and filtered to give Part A compound (183 g,100% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) (2.11 (s, 3H),3.57-3.66 (m, 2H), 4.05-4.12 (m, 1H), 4.21 (t, J=4.83 Hz, 2H).

To crude Part A compound (183 g, 1202 mmol) was added pTsOH (1 g, 5.26mmol), followed by dropwise addition of ethyl vinyl ether (118 mL, 1232mmol) over a period of 2 h. The flask was cooled to maintain a reactiontemperature of 35-37° C. After the addition was complete, the mixturewas heated at 40-45° C. for 18 h, then cooled to RT to give crude Part Bcompound (270 g, 100%) as a red liquid.

To a 110° C. solution of NaOH (110 g, 2750 mmol) in water (110 mL) wasadded Part B compound (270 g, 1202 mmol) over a 1.5 h period. Thereaction mixture was refluxed for another 4 h, then was cooled to RT andwashed with water (110 mL). The aqueous layer was extracted with DCM(110 mL), and the combined organic extracts were concentrated in vacuoto give a brown oil. Distillation (bp=45-50° C. @ 0.5 mm Hg) gave Part Ccompound (15 g, 8.5%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 1.15 (t,J=7.15 Hz, 3H), 1.25 (d, J=5.50 Hz, 3H), 3.44 (dd, J=9.34, 7.15 Hz, 1H),3.56 (q, J=7.15 Hz, 1H), 4.55-4.84 (m, 4H).

A solution of Part C compound (15 g, 103 mmol) in MeOH (5.26 mL, 125mmol) was cooled to 15-18° C., and p-TsOH (100 mg, 0.581 mmol) was addedwith stirring. The reaction mixture was stirred for 45 min, after whichNaHCO₃ (50 mg, 0.595 mmol) was added. Distillation at 35-40° C. (0.1mmHg) gave crude Part D compound (7.0 g, 95%) as a clear oil.

To a well-stirred 50° C. solution of Part D compound (7 g, 94 mmol) andp-TsCl (12.8 g, 67.1 mmol) in water (15 mL) was added dropwise asolution of NaOH (2.69 g, 67.1 mmol) in water (15 mL). The reaction washeated for 1 h at 50° C., then cooled to RT and toluene (10 mL) wasadded. The aqueous layer was extracted with toluene (5 mL×2). Thecombined organic extracts were washed with conc NH₄OH (3×) and water(2×), then concentrated in vacuo. Hexane (50 mL) was added to theresidue and a solid was formed, which was collected by filtration andthen was dried in vacuo for 1 h to give Part E compound (10 g, 65%yield) as a white solid. [M+H]⁺=229.1; ¹H NMR (400 MHz, CDCl₃) δ ppm2.46 (s, 3H), 4.64-4.75 (m, 4H), 5.27-5.34 (m, 1H), 7.37 (d, J=8.25 Hz,2H), 7.78 (d, J=8.25 Hz, 2H).

A mixture of Example 67 Part A compound (450 mg, 1.396 mmol), Part Ecompound (500 mg, 2.190 mmol), and K₂CO₃ (2.7 g, 19.54 mmol) in DMF (5mL) was stirred in a sealed tube at 110° C. for 18 h, then was cooled toRT. The reaction was filtered, the solids were washed with DMF, and thecombined filtrates were concentrated in vacuo. The residue wasneutralized with TFA and purified by preparative HPLC(Phenomenex AXIA 5u C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 30% A to 100% B over 10 min+1 min hold time at100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) togive the Part F compound (220 mg, 42% yield) as a white solid.[M+H]⁺=365.2; ¹H NMR (400 MHz, CDCl₃) δ 3.08 (s, 3H), 4.78 (dd, J=7.15,4.95 Hz, 2H), 5.02 (t, J=6.87 Hz, 2H), 5.23-5.31 (m, 1H), 6.75 (t,J=1.92 Hz, 1H), 7.13 (d, J=8.79 Hz, 2H), 7.18 (s, 1H), 7.39 (s, 1H),7.93 (d, J=8.24 Hz, 2 H).

A mixture of Part F compound (14 mg, 0.038 mmol), Example 13 Part Ecompound (9.62 mg, 0.038 mmol), HOAt (10 mg, 0.072 mmol), EDCI (20 mg,0.500 mmol) and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL) was stirredat 40° C. for 18 h, then was cooled to RT. The reaction mixture waspartitioned between EtOAc (1 mL) and 1N aqueous HCl (1 mL). The organiclayer was dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (Phenomenex AXIA 5 μm C18 30×100 mm column;detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% Ato 100% B over 10 min+1 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound(13 mg, 55.6% yield) as a white solid. [M+H]⁺=597.2; ¹H NMR (400 MHz,CDCl₃) δ 1.28 (t, J=7.03 Hz, 6H), 3.08 (s, 3H), 3.34 (d, J=21.09 Hz,2H), 4.04-4.16 (m, 4H), 4.75 (dd, J=7.47, 4.83 Hz, 2H), 5.05 (t, J=6.81Hz, 2 H), 5.36-5.45 (m, J=5.49, 5.38, 5.33, 5.33 Hz, 1H), 6.82 (t,J=2.20 Hz, 1H), 6.96 (d, J=3.52 Hz, 1H), 7.15 (d, J=8.79 Hz, 2H), 7.24(s, 1H), 7.42 (s, J=1.76, 1.76 Hz, 1 H), 7.94 (d, J=9.23 Hz, 2H).

Example 72

Pre-cooled TFAA (25 mL, 177 mmol) at 0° C. was added to D-malic acid (5g, 37.3 mmol) with stirring. The suspension was stirred for 2 h at RT,then was concentrated in vacuo. Dry benzyl alcohol (25 mL, 240 mmol) wasadded and the solution was stirred overnight at RT. Volatiles (benzylalcohol and TFAA) were removed in vacuo. The residue was chromatographed[SiO₂; EtOAc/Hexane (1:1+0.5% TFA)] to give Part A compound (7.9 g, 94%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.80-2.96 (m, 2H),4.55 (dd, J=6.19, 4.42 Hz, 1H), 5.24 (s, 2 H), 7.30-7.38 (m, 5H);[a]=+12.19@ 1.4% w/v in DMF at 589 nm.

To a solution of the Part A compound (7.9 g, 35.2 mmol) and Et₃N (5.6mL, 40.2 mmol) in Toluene (120 mL) was slowly added Ph₂PON₃ (8.64 mL,40.0 mmol) over ˜30 min. The reaction mixture was refluxed for 2 h,stirred at 70° C. for 2 h, then cooled to RT and stirred at RT for 3days. Volatiles were removed in vacuo; the residue was dissolved inwater and extracted with EtOAc (20 mL×3). The combined organic extractswere washed with sat. aqueous NaHCO₃, dried (Na₂SO₄) and concentrated invacuo. The residue was chromatographed [SiO₂; EtOAc/Hexane (1:1)] togive Part B compound (2.28 g, 27.5% yield) as a pale solid.[M+H]⁺=222.16; ¹H NMR (400 MHz, CDCl₃) δ 3.58-3.73 (m, 1H), 3.86 (t,J=9.35 Hz, 1H), 5.02 (dd, J=9.60, 5.56 Hz, 1H), 5.24 (d, J=1.77 Hz, 2H),6.40 (br. s., 1H), 7.36 (s, 5 H); [a]=−4.56 @ 1.2% w/v in DMF at 589 nm.

To a 0° C. suspension of Part B compound (2.28 g, 10.31 mmol) in EtOH(50 mL) was slowly added NaBH₄ (0.390 g, 10.31 mmol). The mixture wasstirred for 3 h at 0° C., then was warmed to RT and sat. aqueous NH₄Cl(2 mL) was added. The reaction was stirred for 30 min, then the solidswere filtered off, and the filtrate was concentrated in vacuo. Theresidue was chromatographed (SiO₂; EtOAc/MeOH, 5:1) to give Part Ccompound (0.966 g, 80% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d6) δ 3.20 (t, J=7.70 Hz, 1H), 3.41-3.57 (m, 3H), 4.52 (dt,J=15.39, 4.67 Hz, 1H), 5.06 (t, J=5.77 Hz, 1H), 7.39 (br. s., 1H);[a]=−33.11 @ 1.1% w/v in EtOH at 589 nm

To a −5° C. solution of Part C compound (966 mg, 8.25 mmol) and pyridine(10 mL, 124 mmol) in DCM (15 mL) was slowly added MsCl (0.8 mL, 10.27mmol) over 1 h. After 3 h, the volatiles were removed in vacuo at aminimal temperature. The residue was chromatographed (SiO₂; CH₂Cl₂/MeOH95:5 v/v) to give Part D compound (1.5 g, 93% yield) as a colorlesssolid. ¹H NMR (400 MHz, DMSO-d6) δ 3.21-3.27 (m, 4H), 3.58 (t, J=9.34Hz, 1H), 4.28-4.35 (m, 1H), 4.36-4.43 (m, 1 H), 4.80-4.88 (m, 1H), 7.63(br. s., 1H); [a]=−33.93 @ 0.55% w/v in EtOH at 589 nm.

A mixture of Example 26 Part A compound (400 mg, 1.241 mmol), Part Dcompound (242 mg, 1.241 mmol), and K₂CO₃ (2.7 g, 19.54 mmol) in DMF (5mL) was stirred in a sealed tube at 110° C. for 18 h, then was cooled toRT and filtered. The filtrate was concentrated in vacuo. The residue wasneutralized with TFA and then purified by preparative HPLC (PhenomenexAXIA 5 u C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 30% A to 100% B over 10 min+1 min hold time at100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) togive the Part E compound (260 mg, 51.4% yield) as a white solid.[M+H]⁺=408.1; ¹H NMR (400 MHz, CD₃OD) δ 3.12 (s, 3H), 3.55 (dd, J=9.01,6.37 Hz, 1H), 3.75 (t, J=9.23 Hz, 1H), 4.17-4.24 (m, 1H), 4.26-4.33 (m,1H), 4.97-5.05 (m, 1H), 6.98 (t, J=2.20 Hz, 1 H), 7.19 (d, J=8.79 Hz,2H), 7.30 (s, 1H), 7.47 (s, 1H), 7.95 (d, J=9.23 Hz, 2H); [a]=−23.97 @1.4% w/v in MeOH at 589 nm.

A mixture of Part E compound (20 mg, 0.049 mmol), Example 13 Part Ecompound (12.29 mg, 0.049 mmol), HOAt (10 mg, 0.072 mmol), EDCI (20 mg,0.500 mmol), and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL) was stirredat 25° C. for 18 h. Volatiles were removed in vacuo and the residue waspurified by preparative HPLC (Phenomenex AXIA 5 μm C18 30×100 mm column;detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% Ato 100% B over 10 min+1 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound(17 mg, 51.4% yield) as a white solid. [M+H]⁺=640.3; ¹H NMR (400 MHz,CDCl₃) δ 1.31 (td, J=7.07, 5.05 Hz, 6H), 3.07 (s, 3H), 3.32 (d, J=21.22Hz, 2H), 3.64 (dd, J=8.84, 6.32 Hz, 1H), 3.82 (t, J=8.97 Hz, 1H),4.07-4.18 (m, 4H), 4.38 (d, J=4.55 Hz, 2H), 4.96-5.06 (m, 1H), 6.12 (br.s., 1H), 6.93 (t, J=2.27 Hz, 1H), 6.99 (d, J=3.79 Hz, 1H), 7.15 (d,J=8.84 Hz, 2H), 7.50 (dd, J=2.15, 1.39 Hz, 1H), 7.71 (t, J=1.77 Hz, 1H),7.92 (d, J=8.84 Hz, 2H); e.e.=98.2% (Chiralpak AS, 250×4.6 mm ID; 10 nm,RT, 60% (50/50 MeOH-EtOH): 40% Heptane, 1 mL/min)

Example 73

The title compound (22 mg; 58% yield; white solid) was synthesized fromL-malic acid employing the same procedure as described in Example 72.[M+H]⁺=640.3; ¹H NMR (400 MHz, CDCl₃) δ 1.33 (t, J=7.07 Hz, 6H), 3.07(s, 3H), 3.38 (d, J=21.47 Hz, 2H), 3.64 (dd, J=8.84, 6.57 Hz, 1H), 3.81(t, J=8.97 Hz, 1H), 4.17 (dd, J=8.21, 7.20 Hz, 3H), 4.29-4.37 (m, 1H),4.40-4.48 (m, 1H), 4.99-5.08 (m, 1H), 5.91 (br. s., 1H), 6.96 (t, J=2.15Hz, 1H), 7.06 (d, J=3.79 Hz, 1H), 7.15 (dq, J=8.84, 4.80 Hz, 1H), 7.51(dd, 1H), 7.71 (t, J=1.52 Hz, 1H), 7.93 (dq, J=8.84, 4.80 Hz, 1H);e.e.=99.9% (Chiralpak AS, 250×4.6 mm ID; 10 μm, RT, 60% (50/50MeOH-EtOH): 40% Heptane, 1 mL/min)

Example 74

A mixture of 2-(2,4-dimethoxyphenyl)acetic acid (20 mg, 0.12 mmol),Example 13 Part E compound (25 mg, 0.1 mmol), HOAt (20 mg, 0.015 mmol),EDCI (25 mg, 0.500 mmol), and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL)was stirred at 25° C. for 18 h. The reaction mixture was concentrated invacuo, and the residue was purified by preparative HPLC (Phenomenex AXIA5 μm C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 30% A to 100% B over 10 min+1 min hold time at100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) togive the title compound (2.6 mg, 6% yield) as a yellow oil.[M+H]⁺=429.4; ¹H NMR (400 MHz, CDCl₃) δ 1.31 (t, J=7.03 Hz, 6H),3.25-3.34 (d, J=21.53 Hz, 2H), 3.79 (s, 3H), 3.80 (s, 3H), 3.83 (s, 2H),4.09-4.18 (m, 4H), 6.46-6.50 (m, 2H), 6.91 (d, J=3.52 Hz, 1H), 7.15 (d,1H);

Examples 75 to 77

The following examples were prepared in the same manner as Example 74:

Yield and Example # Structure [M + H]⁺ 1H NMR (400 MHz, CDCl₃)Description 75

429.4 δ 1.29 (t, J = 7.03 Hz, 6 H), 3.27 (d, J = 21.09 Hz, 2 H),3.83-3.91 (m, 8 H), 4.04- 4.17 (m, 4 H), 6.83-6.93 (m, 3 H), 7.01-7.08(m, 1 H) 8.3 mg (19% yield); yellow oil 76

429.4 (1.27 (t, J = 7.03 Hz, 6 H), 3.25 (d, J = 21.09 Hz, 2 H),3.75-3.78 (m, 2 H), 3.79 (s, 6 H), 4.02-4.12 (m, 4 H), 6.40-6.43 (m, 1H), 6.47 (d, J = 2.20 Hz, 2 H), 6.82 (none, 1 H) 8.6 mg (20% yield);yellow oil 77

429.4 δ 1.29 (t, J = 7.03 Hz, 6 H), 3.23-3.31 (m, 2 H), 3.77 (s, 3 H),3.82 (s, 5 H),4.06- 4.14 (m, 4 H), 6.82-6.87 (m, 4 H) 8.3 mg (19%yield); yellow oil

Example 78

A solution of Example 26C acid (146 mg, 0.384 mmol) and (COCl)₂ (2 mL ofa 2M solution in DCM, 4 mmol) in DCM (2 mL) was stirred at RT for 18 h,then was concentrated in vacuo. The crude acid chloride was taken up inEt₂O (5 mL) and was added dropwise to a 0° C. solution of CH₂N₂ in Et₂O(5 mL) prepared from 1-methyl-3-nitro-1-nitrosoguanidine (735 mg, 5mmol) and 40% aqueous KOH (0.8 g, 15 mmol, 2 mL water) at 0° C. Thereaction mixture was stirred at RT for 1 h and was concentrated under astream of air; residual solvent were removed in vacuo. The residue waschromatographed (SiO₂; EtOAc/Hexane 5:1) to give Part A compound (130mg, 84% yield) as a yellow oil. [M+H]⁺=405.2; ¹H NMR (400 MHz, CDCl₃) δ1.28 (d, J=6.15 Hz, 3H), 3.03 (s, 3H), 3.36 (s, 3H), 3.43-3.57 (m, 2H),4.51-4.62 (m, 1H), 5.86 (s, 1H), 6.79 (t, J=2.20 Hz, 1H), 6.99 (s, 1H),7.08 (d, J=8.79 Hz, 2H), 7.15 (s, 1H), 7.87 (d, 2H).

To a −25° C. solution of Part A compound (130 mg, 0.321 mmol) and BnOH(0.5 mL, 5 mmol) in dry THF (2 mL) was added over 15 min a solution ofPhCO₂Ag (206.1 mg, 0.9 mmol) in Et₃N (1.67 mL, 12 mmol). The reactionmixture was stirred at RT for 5 h in the dark. The reaction was filteredthrough Celite®; the filtrate was concentrated in vacuo, and the residuewas chromatographed [SiO₂; EtOAc/Hexane(2:1)] to give Part B compound(130 mg, 83.6%) as a clear oil. [M+H]⁺=485.2; ¹H NMR (400 MHz, CDCl₃) δ1.28 (d, J=6.15 Hz, 3H), 3.05 (s, 3H), 3.39 (s, 3H), 3.44-3.50 (m, 1H),3.52-3.58 (m, 1H), 3.62 (s, 2H), 4.45-4.54 (m, 1H), 5.14 (s, 2H), 6.56(t, J=2.20 Hz, 1H), 6.59 (t, J=1.76 Hz, 1H), 6.73 (d, J=1.76 Hz, 1H),7.08 (d, J=9.23 Hz, 2H), 7.28-7.38 (m, 5H), 7.86 (d, J=8.79 Hz, 2H).

A solution of Part B compound (130 mg, 0.268 mmol) and 10% Pd—C (20 mg)in EtOAc (10 mL) was stirred under H₂ (g; 60 psi) for 18 h. The catalystwas removed by filtration and the filtrate was concentrated in vacuo togive Part C compound (86 mg, 81.4%) as a clear oil. [M+H]⁺=395.1; ¹H NMR(400 MHz, CDCl₃) δ 1.28 (d, J=6.15 Hz, 3H), 3.05 (s, 3H), 3.38 (s, 3H),3.44-3.51 (m, 1H), 3.51-3.57 (m, 1H), 3.58 (s, 2H), 4.46-4.56 (m, 1H),6.55 (t, J=2.20 Hz, 1H), 6.58 (s, 1H), 6.72 (s, 1H), 7.09 (d, J=8.79 Hz,2H), 7.87 (d, 2H).

A solution of Part C compound (43 mg, 0.109 mmol) and (COCl)₂ (3.0 mL ofa 2M solution in DCM, 6 mmol) in DCM (3 mL) was stirred at RT for 18 h,then was concentrated in vacuo. The crude acid chloride was taken up inDCM (2 mL) and was added over 15 min to a 0° C. solution of Example 13Part E compound (37 mg, 0.148 mmol) and pyridine (0.2 mL, 2.5 mmol) inDCM (3 mL). The reaction was stirred at 0° C. for 30 min, then wasconcentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex AXIA 5 μm C18 30×100 mm column; detection at 220 nm; flowrate=40 mL/min; continuous gradient from 30% A to 100% B over 10 min+1min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (20 mg, 29% yield) as a yellowoil. [M+H]⁺=627.3; ¹H NMR (400 MHz, CDCl₃) δ 1.21-1.34 (m, 6H), 3.06 (s,3H), 3.23-3.34 (m, 2H), 3.38 (s, 3H), 3.44-3.51 (m, 1H), 3.51-3.59 (m,1H), 3.77 (s, 2H), 4.03-4.15 (m, 4H), 4.46-4.58 (m, 1H), 6.58 (t, J=2.20Hz, 1 H), 6.64 (s, 1H), 6.79 (s, 1H), 6.85 (d, J=3.52 Hz, 1H), 7.11 (d,J=8.79 Hz, 2H), 7.88 (d, 2H).

Example 79

A solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (20 mg,0.11 mmol), Example 13 Part E compound (20 mg, 0.083 mmol), HOAt (20 mg,0.147 mmol), EDCI (40 mg, 0.21 mmol), and DIPEA (40 mg, 0.31 mmol) inDMF (1 mL) was stirred at 25° C. for 18 h. The reaction mixture wasconcentrated in vacuo, and the residue was purified by preparative HPLC(Phenomenex AXIA 5 u C18 30×100 mm column; detection at 220 nm; flowrate=40 mL/min; continuous gradient from 30% A to 100% B over 10 min+1min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (8.2 mg, 24% yield) as a whitesolid. [M+H]⁺=413.3; ¹H NMR (400 MHz, CDCl₃) δ 1.29 (t, J=7.03 Hz, 6H),3.27-3.36 (d, J=21.09 Hz, 2H), 4.06-4.16 (m, 4H), 4.28-4.37 (m, 4H),6.94 (d, J=3.52 Hz, 1H), 6.99 (d, J=8.35 Hz, 1H), 7.64-7.71 (m, 2H).

Example 80

A mixture of methyl 3,5-dihydroxybenzoate (200 mg, 1.189 mmol), Example71 Part E compound (600 mg, 2.63 mmol), and K₂CO₃ (2 g, 14.47 mmol) inDMF (10 mL) was stirred in a sealed tube at 115° C. for 18 h, then wascooled to RT. Solids were removed by filtration and were washed withDMF. The combined filtrates were concentrated in vacuo. The residue wasneutralized with TFA and was purified by preparative HPLC (PhenomenexAXIA 5 u C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 30% A to 100% B over 10 min+1 min hold time at100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) togive Part A compound (60 mg, 19.0%) as a white solid. [M+H]⁺=267.2; ¹HNMR (400 MHz, CD₃OD) δ 4.68 (dd, J=7.15, 4.95 Hz, 4H), 5.02 (t, J=6.60Hz, 4H), 5.26-5.35 (m, 2H), 6.46 (t, J=2.20 Hz, 1H), 6.98 (d, J=2.20 Hz,2H).

A mixture of Part A compound (21 mg, 0.079 mmol), Example 13 Part Ecompound (19.74 mg, 0.079 mmol), HOAt (20 mg, 0.145 mmol), EDCI (20 mg,0.500 mmol), and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL) was stirredat 25° C. for 18 h, then was concentrated in vacuo. The residue waspurified by preparative HPLC (Phenomenex AXIA 5 u C18 30×100 mm column;detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% Ato 100% B over 10 min+1 min hold time at 100% B, where A=90:10:0.1H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound(25 mg, 63.6% yield) as a white solid. [M+H]⁺=499.3; ¹H NMR (400 MHz,CDCl₃) (7.09 (2H, d), 7.03 (1 H, d, J=3.30 Hz), 6.54 (1H, t, J=2.20 Hz),5.31-5.39 (2H, m), 5.04 (4H, t, J=6.60 Hz), 4.74 (4H, dd, J=7.70, 4.95Hz), 4.10-4.19 (4H, m), 3.36 (1H, s), 3.31 (1H, s), 1.32 (6H, t, J=6.87Hz).

Example 81

A mixture of methyl 3-hydroxy-5-isopropoxybenzoate (100 mg, 0.476 mmol),Example 71 Part E compound (180 mg, 0.789 mmol), and K₂CO₃ (1 g, 7.24mmol) in DMF (5 mL) was stirred in a sealed tube at 115° C. for 18 h,then was cooled to RT. Solids were filtered off and washed with DMF. Thecombined filtrates were concentrated in vacuo. The residue wasneutralized with TFA and purified by preparative HPLC (Phenomenex AXIA 5μm C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 30% A to 100% B over 10 min+1 min hold time at100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) togive Part A compound (100 mg, 83% yield) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 1.35 (d, J=6.05 Hz, 6H), 4.59 (dt, J=12.09, 6.05 Hz, 1H),4.77 (dd, J=7.42, 5.22 Hz, 2H), 5.01 (t, J=6.60 Hz, 2H), 5.19-5.27 (m,1H), 6.52 (t, J=2.47 Hz, 1H), 6.94 (s, 1H), 7.27 (s, 1H).

A mixture of Part A compound (21 mg, 0.083 mmol), Example 13 Part Ecompound (20.83 mg, 0.083 mmol), HOAt (20 mg, 0.145 mmol), EDCI (20 mg,0.500 mmol), and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL) was stirredat 25° C. for 18 h, then was concentrated in vacuo. The residue wasneutralized with TFA and was purified by preparative HPLC (PhenomenexAXIA 5 μm C18 30×100 mm column; detection at 220 nm; flow rate=40mL/min; continuous gradient from 30% A to 100% B over 10 min+1 min holdtime at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (28 mg, 0.058 mmol, 69.4%yield) as a clear wax. [M+H]⁺=485.3; ¹H NMR (400 MHz, CDCl₃) δ 7.31 (1H,t, J=1.52 Hz), 6.96-7.01 (2H, m), 6.56 (1H, t, J=2.27 Hz), 5.28-5.35(1H, m, J=5.53, 5.53, 5.49, 5.43 Hz), 5.03 (2H, t, J=6.95 Hz), 4.64-4.78(3H, m), 4.13 (4H, dd, J=8.21, 7.20 Hz), 3.36 (1H, s), 3.30 (1H, s),1.35 (6H, d, J=6.06 Hz), 1.30 (6H, t, J=7.07 Hz).

Example 82

To a solution of tert-butyl 4-(chloromethyl)thiazol-2-ylcarbamate (249mg, 1.00 mmol) and CH₃P(OEt)₂ (124.2 mg, 1.00 mmol) in MeCN (4.0 mL)under Ar at RT was added 18-crown-6 (52.9 mg, 0.2 mmol), K₂CO₃ (138.2mg, 1.00 mmol), and (n-Bu)₄NI (74.0 mg, 0.20 mmol). The reaction mixturewas heated at 55° C. for 2 h, then cooled to RT and quenched withsaturated aqueous NaHCO₃. The mixture was extracted with EtOAc (2×). Thecombined organic extracts were washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residual oil was chromatographed (SiO₂;continuous gradient from 0% EtOAc/Hexane to 100% EtOAc/Hexane) toprovide Part A compound (171 mg, 51% material balance, 90% purity byHPLC) as a colorless oil.

To a RT solution of Example 82 Part A compound (171 mg, ˜0.51 mmol) inCH₂Cl₂ (1.5 mL) [Note: the flask was fitted with a CaCl₂-filled dryingtube to protect from atmospheric moisture] was added TFA (0.5 mL). Thereaction was stirred at RT for 14 h, then was concentrated in vacuo andthen stripped from CH₂Cl₂. The oily residue was used without furtherpurification or characterization for Part C.

A RT solution of Example 26 Part C acid (193.4 mg, 0.51 mmol) in CH₂Cl₂(2.0 mL) [Note: the flask was fitted with a CaCl₂-filled drying tube toprotect from atmospheric moisture] was treated with oxalyl chloride(0.305 mL of a 2 M solution in CH₂Cl₂, 0.61 mmol) and DMF (0.020 mL).The reaction mixture was stirred at RT for 2 h, then was concentrated invacuo, and re-dissolved in CH₂Cl₂ (2 mL). To this RT solution under Arwas added a solution of Part B compound in CH₂Cl₂ (2 mL), followed byEt₃N (0.213 mL, 1.53 mmol). After 15 h at RT, the reaction mixture wasdiluted with CH₂Cl₂ and washed with sat. aqueous NaHCO₃. The organicextract was dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by preparative HPLC (Phenomenex Luna 5 u C18 30×250 mm column;detection at 220 nm; flow rate=30 mL/min; continuous gradient from 20% Bto 100% B over 20 min+5 min hold time at 100% B, where A=90:10:0.1 H₂O:CH₃CN:TFA and B=10:90:0.1 H₂O:CH₃CN:TFA) to provide the title compound(33 mg, 11%) as a colorless thick oil. [M+H]⁺=599.2; ¹H NMR (400 MHz,CDCl₃): δ 11.23 (br s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.57 (t, J=1.6 Hz,1H), 7.47 (t, J=1.6 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 6.95 (s, 1H), 6.87(t, J=2.2 Hz, 1H), 5.22 (m, 2H), 4.68 (m, 1H), 4.05 (m, 2H), 3.56 (ddd,J=6.6, 10.5, 30.3 Hz, 2H), 3.39 (s, 1H), 3.09 (s, 1H), 1.51 (dd, J=13.7,17.6 Hz, 3H), 1.34 (d, J=6.6 Hz, 3H), 1.27 (dt, J=2.2, 7.2 Hz, 3H).

Example 83

To a stirred solution of ethyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate (2.24 g, 8.23 mmol) in CH₂Cl₂ (25 mL) under Ar at−78° C. was added a solution of DiBALH (25.5 mL, 1.0 M in CH₂Cl₂, 25.5mmol) at such a rate as to keep the temperature ≦−65° C. The reactionwas stirred for 20 min at −65° C., then was allowed to warm to −30° C.After 30 min, the reaction mixture was quenched with 1 M sodiumpotassium tartrate solution (30 mL), warmed to RT and stirred for 2 h atRT. The mixture was filtered through Celite®, which was washed withCH₂Cl₂. The combined filtrates were dried (Na₂SO₄), and concentrated invacuo. The resulting oil was chromatographed (SiO₂; continuous gradientfrom 0% EtOAc/Hexane to 100% EtOAc/Hexane) to provide Part A compound(1.66 g, 88% yield) as an amorphous white solid.

To a 0° C. solution of Part A compound (310 mg, 1.35 mmol) in CH₂Cl₂ (5mL) under Ar was added dimethylphosphinic chloride (182 mg, 1.62 mmol),and then Et₃N (0.244 mL, 1.75 mmol) over 2 min. The reaction was allowedto warm to RT and stirred at RT for 14 h, then was diluted with EtOAc.The mixture was washed with 1% aqueous HCl and brine. The organic phasewas dried (MgSO₄) and concentrated in vacuo to give Part B compound as acolorless oil (413 mg, 100% crude). This material was used in the nextstep without further purification.

C1: To a stirred solution of Part B compound (410 mg, 1.34 mmol) inCH₂Cl₂ (3 mL) at RT [Note: the flask was fitted with a CaCl₂-filleddrying tube to protect from atmospheric moisture] was added TFA (1 mL).The reaction was stirred for 14 h at RT, and the reaction mixture wasconcentrated in vacuo and re-dissolved in MeOH (5 mL). The solution waspassed through 2 StratroSpheres™ PL-HCO₃ MP SPE cartridges (0.9 meqcapacity), and the eluant was evaporated in vacuo to provide Part C1compound. The resulting colorless oil (225 mg) was re-dissolved inCH₂Cl₂ (2 mL). One half (by weight) of this solution was used withoutfurther characterization for Part C2.

C2: To a stirred slurry of Example 26 Part C compound (152 mg, 0.40mmol) and HOAt (54.5 mg, 0.40 mmol) in CH₂Cl₂ (2.4 mL) at RT under Arwas added EDC (76.3 mg, 0.40 mmol). A clear solution soon formed. After30 min, the solution of Part C1 compound in CH₂Cl₂ from Cl was added,followed by iPr₂NEt (0.028 mL, 0.20 mmol) and DMAP (5 mg, 0.04 mmol).The reaction was stirred for 16 h at RT, then was quenched with sat.aqueous NH₄Cl and extracted twice with EtOAc. The combined organicextracts were dried (Na₂SO₄) and evaporated in vacuo to give an orangeoil. The residue was purified by preparative HPLC (Phenomenex AXIA Luna5 u 30×75 mm column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 0% B to 100% B over 10 min+10 min hold time at60% B, where A=90:10:0.1 H₂O: CH₃CN:TFA and B=10:90:0.1 H₂O:CH₃CN:TFA)to provide the title compound (28.9 mg, 13% yield) as a waxy whitesolid. [M+H]⁺=569.0; ¹H NMR (400 MHz, CDCl₃) δ 11.75 (br s, 1H), 7.92(d, J=8.8 Hz, 2H), 7.63 (t, J=2.2 Hz, 1H), 7.49 (t, J=1.9 Hz, 1H), 7.14(d, J=8.8 Hz, 2H), 6.94 (s, 1H), 6.87 (t, J=2.2 Hz, 1H), 5.20 (d, J=7.7Hz, 2H), 4.70 (m, 1H), 3.55 (ddd, J=6.0, 9.9, 30.2 Hz, 2H), 3.40 (s,1H), 3.08 (s, 1H), 1.53 (dd, J=2.8, 14.3 Hz, 6H), 1.33 (d, J=6.6 Hz,3H).

Example 84

To a 0° C. solution of Example 26 Part A compound (100 mg, 0.310 mmol),Ph₃P (150 mg, 0.572 mmol), and oxetan-2-ylmethanol (40 mg, 0.454 mmol)in THF (5 mL) was added DIAD (0.2 mL, 1.029 mmol). The reaction wasstirred at RT for 18 h, and volatiles were removed in vacuo. The residuewas chromatographed (EtOAc/Hexane, 1:1) to give the crude methyl ester.To a solution of this material in MeOH (1 mL) was added 1N aqueous NaOH(1 mL). The reaction was stirred at RT for 2 h and then acidified withTFA and concentrated in vacuo. The residue was purified by preparativeHPLC (Phenomenex AXIA 5 u C18 30×100 mm column; detection at 220 nm;flow rate=40 mL/min; continuous gradient from 30% A to 100% B over 10min+1 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to give Part A compound (40 mg, 34.1% yield)as a white solid. [M+H]⁺=377.2; ¹H NMR (400 MHz, CDCl₃) δ 2.66-2.88 (m,2H), 3.08 (s, 3H), 4.20 (d, J=3.85 Hz, 2H), 4.66-4.81 (m, 2H), 5.16-5.25(m, 1H), 6.92 (t, J=2.47 Hz, 1H), 7.11 (d, J=8.79 Hz, 2H), 7.36 (d,J=2.20 Hz, 1H), 7.52 (dd, J=2.20, 1.10 Hz, 1H), 7.92 (d, J=8.79 Hz, 2H).

A mixture of Part A compound (15 mg, 0.040 mmol), Example 13 Part Ecompound (20 mg, 0.080 mmol), HOAt (20 mg, 0.145 mmol), EDCI (40 mg,1.000 mmol) and DIPEA (0.2 mL, 1.148 mmol) in DMF (0.5 mL) was stirredat 25° C. for 18 h. The reaction mixture was concentrated in vacuo, andthe crude residue was purified by preparative HPLC (Phenomenex AXIA 5 uC18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min;continuous gradient from 30% A to 100% B over 10 min+1 min hold time at100% B, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) toprovide the title compound (9.8 mg, 0.016 mmol, 39.7% yield) as a whitesolid. [M+H]⁺=611.3; ¹H NMR (400 MHz, CDCl₃) δ 7.93 (2H, d, J=8.79 Hz),7.59 (1H, s), 7.39 (1H, s), 7.15 (2H, d, J=8.79 Hz), 6.94-6.98 (2H, m),5.12-5.20 (1H, m), 4.62-4.78 (2H, m), 4.22-4.32 (2H, m), 4.06-4.17 (4H,m, J=7.35, 7.35, 7.28, 7.15 Hz), 3.32 (2H, d, J=20.89 Hz), 3.08 (3H, s),2.64-2.86 (2H, m), 1.30 (6H, t, J=6.87 Hz).

Example 85

To a solution of KOtBu (17.1 mL, 17.1 mmol) in t-BuOH (10 mL) was addeddropwise dimethyl malonate (2.0 mL, 17.1 mmol). To the resulting mixturewas added a warm solution of 1-chloro-4-(methylsulfonyl) 2-nitrobenzene(2.0 g, 8.6 mmol) in t-BuOH (10 mL). The reaction mixture was heated atreflux for 15 h, then was cooled to RT and diluted with EtOAc (50 mL),washed with water and brine (30 mL each), dried (MgSO₄) and concentratedin vacuo to provide Part A compound (2.8 g, 100%).

To a solution of Part A compound (2.8 g, 8.6 mmol) in DMSO (10 mL) wasadded NaCl (1.0 g, 17.1 mmol) and water (2 mL, 111 mmol). The mixturewas heated at 120° C. for 5 h, then was cooled to RT and diluted withEtOAc (50 mL). The organic layer was washed with water and brine (35 mLeach), dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed (SiO₂; 30 min gradient from 100% to 0% hexane/EtOAc) toprovide Part B compound (863 mg, 37% yield over 2 steps).

To a solution of Part B compound (830 mg, 3.0 mmol) and Ac₂O (2.0 mL,21.6 mmol) in toluene (10 mL) was slowly added 10% Pd/C (200 mg, 1.7mmol). The reaction was stirred under an atmosphere of H₂ (g) (1 atm) atRT for 4 h. The catalyst was filtered off and washed with toluene (2×).The combined filtrates were concentrated in vacuo to provide crude PartC compound (398 mg, 46%).

To a 90-95° C. solution of Part C compound (398 mg, 1.4 mmol) in AcOH (6mL) was added dropwise t-butyl nitrite (0.18 mL, 1.5 mmol). The reactionwas stirred at 95° C. for 30 min. The reaction was cooled to RT and wasdiluted with EtOAc (30 mL). The organic layer was washed with water (15mL) and brine (15 mL), dried (MgSO₄), and concentrated in vacuo until asolid precipitated. This solid precipitate was collected by filtrationand washed with toluene to give Part D compound (280 mg, 79% yield),which was used in the next step without further purification.

To a solution of Part D compound (30 mg, 0.12 mmol) in CH₃CN (1.5 mL)was added 1-(chloromethyl)-4-(methylsulfonyl)benzene (72.4 mg, 0.35mmol), K₂CO₃ (48.9 mg, 0.35 mmol), and (n-Bu)₄NI (3.5 mg, 9.4 μmol). Thereaction was stirred at 80° C. for 3 h, then cooled to RT. Solids werefiltered off and washed with acetone. The combined filtrates wereconcentrated in vacuo to afford a mixture of the Part E compounds.

To a solution of Part E compounds (0.12 mmol theoretical yield) in THF(1 mL) was added 1N aqueous NaOH (0.4 mL, 0.40 mmol). The reaction wasstirred at RT for 15 h., then was diluted with EtOAc (4 mL) andacidified with 1N aqueous HCl (0.45 mL). The organic layer was washedwith brine, dried (MgSO₄) and concentrated in vacuo. The crude mixturewas purified by preparative HPLC (Phenomenex Luna AXIA 30×100 mm column;detection at 220 nm; flow rate=25 mL/min; continuous gradient from 60% Ato 100% B over 10 min, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to provide Part F1 compound (15.2 mg, 32% yield over 2steps) and Part F2 compound (9.0 mg, 19% yield over 2 steps).

To a solution of Part F1 compound (7 mg, 0.02 mmol) in CH₂Cl₂ (0.8 mL)was added oxalyl chloride (0.03 mL of a 2M solution in DCM, 0.05 mmol)and DMF (1.3 μL, 0.02 mmol). The reaction was stirred at RT for 1 h,then was concentrated in vacuo. The residue was taken up in THF (0.4 mL)and added to a solution of Example 13 Part E compound (17.2 mg, 0.07mmol) and NaHCO₃ (7.2 mg, 0.09 mmol) in THF/H₂O (1:1, 0.8 mL). Thereaction was stirred at RT for 2 h, then was diluted with EtOAc (4 mL)and water (1 mL). The organic layer was concentrated in vacuo. Theresidue was purified by preparative HPLC (Phenomenex Luna AXIA 30×100 mmcolumn; detection at 220 nm; flow rate=40 mL/min; continuous gradientfrom 70% A to 100% B over 10 min, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to provide the title compound (0.63 mg, 5.7%yield) as a white solid. [M+H]⁺=641.2; ¹H NMR (400 MHz, CDCl₃) δ 8.63(1H, d, J=8.35 Hz), 8.21 (1H, s), 7.96 (2H, d, J=8.35 Hz), 7.90 (1H, d,J=8.35 Hz), 7.63 (2H, d, J=8.35 Hz), 6.94-7.04 (1H, m), 5.81 (2H, s),4.05-4.21 (4H, m), 3.35 (2 H, d, J=21.09 Hz), 3.16 (3H, s), 3.05 (3H,s), 1.33 (6H, t, J=7.03 Hz).

Examples 86 to 92

The following Examples were synthesized from Example 85 Part D compoundby employing the general synthetic route described for the preparationof Example 85 compound from Example 85 Part D compound.

Yield and Example # Structure [M + H]⁺ ¹H NMR Description 86

527.0 (400 MHz, CDCl₃) δ 8.62 (1 H, d, J = 8.79 Hz), 8.24 (1 H, s), 7.86(1 H, d, J = 8.35 Hz), 6.94 (1 H, d, J = 3.95 Hz), 4.41 (2 H, d, J =7.03 Hz), 4.04-4.21 (4 H, m), 3.35 (2 H, d, J = 21.09 Hz), 3.16 (3 H,s), 1.41-1.52 (1 H, m), 1.32 (6 H, t, J = 7.03 Hz), 0.66-0.75 (2 H, m),0.50- 0.58 (2 H, m) 4.0 mg (24% yield), white solid 87

581.1 (400 MHz, CDCl₃) δ 8.62 (1 H, d, J = 7.91 Hz), 8.18 (1 H, s),7.79-7.89 (1 H, m), 7.34 (2 H, dd, J = 8.57, 5.05 Hz), 7.06 (2 H, t, J =8.57 Hz), 6.92 (1 H, d, J = 3.52 Hz), 5.67 (2 H, s), 4.02-4.20 (4 H, m),3.34 (2 H, d, J = 21.09 Hz), 3.13 (3 H, s), 1.31 (6 H, t, J = 7.03 Hz)8.5 mg (37% yield), grey solid 88

555.1 (500 MHz, CDCl₃) δ 8.60 (1 H, d, J = 7.70 Hz), 8.22 (1 H, s), 7.85(1 H, d, J = 7.15 Hz), 6.96 (1 H, d, J = 3.85 Hz), 4.46 (2 H, d, J =7.15 Hz), 4.06-4.21 (4 H, m), 3.35 (2 H, d, J = 20.89 Hz), 3.17 (3 H,s), 2.62-2.75 (1 H, m), 1.68-1.81 (4 H, m), 1.57- 1.68 (2 H, m), 1.34-1.43 (2 H, m), 1.32 (6 H, t, J = 7.15 Hz) 8.5 mg (40% yield), whitesolid 89

527.0 (500 MHz, CDCl₃) δ ppm 8.56 (1 H, s), 8.05 (1 H, d, J = 8.80 Hz),7.75 (1 H, d, J = 9.35 Hz), 7.07 (1 H, d, J = 3.30 Hz), 4.77 (2 H, d, J= 7.15 Hz), 4.08-4.24 (4 H, m), 3.38 (2 H, d, J = 21.44 Hz), 3.12 (3 H,s), 1.46-1.63 (1 H, m), 1.26-1.37 (6 H, m), 0.51- 0.65 (4 H, m) 3.0 mg(21% yield), oil 90

555.1 (500 MHz, CDCl₃) δ 8.54 (1 H, s), 8.06 (1 H, d, J = 8.80 Hz), 7.74(1 H, d, J = 9.35 Hz), 7.05 (1 H, d, J = 3.30 Hz), 4.87 (2 H, d, J =7.70 Hz), 4.09-4.21 (4 H, m), 3.36 (2 H, d, J = 21.44 Hz), 3.12 (3 H,s), 2.56-2.71 (1 H, m), 1.64-1.76 (4 H, m), 1.51- 1.63 (2 H, m), 1.35-1.43 (2 H, m), 1.32 (6 H, t, J = 7.15 Hz) 3.5 mg (29% yield), oil 91

571.3 (500 MHz, CDCl₃) δ 8.57 (1 H, d, J = 8.25 Hz), 8.22 (1 H, s), 7.88(1 H, d, J = 9.90 Hz), 7.04 (1 H, d, J = 3.85 Hz), 4.43 (2 H, d, J =7.15 Hz), 4.12-4.24 (4 H, m), 4.01 (2 H, dd, J = 11.55, 2.75 Hz), 3.43-3.49 (2 H, m), 3.40 (2 H, d, J = 21.44 Hz), 3.18 (3 H, s), 2.51-2.68 (1H, m), 1.43-1.64 (4 H, m), 1.34 (6 H, t, J = 7.15 Hz) 10.5 mg (37%yield), grey solid 92

571.3 (500 MHz, CDCl₃) δ 8.55 (1 H, s), 8.04 (1 H, d, J = 8.80 Hz), 7.76(1 H, d, J = 10.45 Hz), 7.12 (1 H, d, J = 3.85 Hz), 4.81 (2 H, d, J =7.15 Hz), 4.13-4.28 (4 H, m), 3.99-4.08 (2 H, m), 3.33-3.48 (4 H, m),3.13 (3 H, s), 2.32- 2.53 (1 H, m), 1.48-1.65 (4 H, m), 1.36 (6 H, t, J= 6.87 Hz) 4.8 mg (24% yield), yellow oil

Example 93

To a solution of Example 13 Part E compound (50 mg, 0.20 mmol) in DCM (1mL) was added 1-benzyl-3-tert-butyl-1H-pyrazole-5-carbonyl chloride(71.9 mg, 0.26 mmol) and pyridine (0.02 mL, 0.26 mmol). The reaction wasstirred at RT for 16 h, then was concentrated in vacuo. The residue waspurified by preparative HPLC (Phenomenex Luna AXIA 30×100 mm column;detection at 220 nm; flow rate=40 mL/min; continuous gradient from 50% Ato 100% B over 10 min, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (64 mg, 65% yield) as an oil.[M+H]⁺=491.1; ¹H NMR (400 MHz, CDCl₃) δ 7.31 (1H, s), 7.17-7.30 (5H, m),6.96 (1H, d, J=3.52 Hz), 5.81 (2H, s), 4.05-4.19 (4H, m), 3.31 (2H, d,J=21.09 Hz), 1.36 (9H, s), 1.29 (6H, t, J=7.03 Hz).

Example 94

To a solution of ethyl trimethylacetopyruvate (205 mg, 1.02 mmol) in dryEtOH (1 mL) was added O-methylhydroxylamine hydrochloride (90 mg, 1.07mmol) and 3 A mol. sieves. The reaction was stirred at RT for 15 h, thenwas filtered and washed with EtOH. The filtrated was concentrated invacuo, and the residue was partitioned between Et₂O and sat. aqueousNaHCO₃. The Et₂O layer was washed with water and brine, dried (MgSO₄)and concentrated in vacuo to give Part A compound (176 mg, 75%) as ared-orange oil.

To a solution of Part A compound (176 mg, 0.77 mmol) in AcOH:EtOH (1.5mL) was added (4-(methylsulfonyl)phenyl)hydrazine (286 mg, 1.54 mmol).The reaction was stirred at 90° C. for 10 h, then was cooled to RT. Thereaction mixture was concentrated in vacuo, and the residue waspartitioned between EtOAc and 0.2 N aqueous HCl. The organic layer waswashed with water and brine, dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; 15 min gradient from 0%EtOAc/Hexanes to 100% EtOAc/Hexanes) to provide Part B1 compound (214mg, 80%) and Part B2 compound (20 mg, 7%).

To a solution of the Part B1 compound (23 mg, 0.07 mmol) in THF (1 mL)was added 1N aqueous NaOH. The mixture was stirred at RT for 15 h, thenwas diluted with EtOAc (4 mL) and acidified with 1N aqueous HCl (0.5mL). The organic layer was washed with brine, dried (MgSO₄) andconcentrated in vacuo to give crude Part C compound (23 mg, 109%recovery).

To a solution of Part C compound (21.3 mg, 0.07 mmol) in DMF (1 mL) wasadded Example 13 Part E compound (33.0 mg, 0.13 mmol), EDCI (25.3 mg,0.13 mmol), HOBT (20.2 mg, 0.13 mmol), and Hunig's Base (0.034 mL, 0.20mmol). The reaction mixture was stirred at RT for 4 days and waspurified directly by preparative HPLC (Phenomenex Luna AXIA 30×100 mmcolumn; detection at 220 nm; flow rate=40 mL/min; continuous gradientfrom 50% A to 100% B over 10 min, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to provide the title compound (14 mg, 38%yield) as a yellow oil. [M+H]⁺=555.1; ¹H NMR (500 MHz, CDCl₃) δ 8.11(2H, d), 7.71 (2H, d, J=8.25 Hz), 6.99 (1H, s), 6.98 (1H, d, J=3.85 Hz),4.10-4.18 (4H, m), 3.98 (1H, s), 3.35 (2H, d, J=21.44 Hz), 3.13 (3H, s),1.30 (6H, t, J=7.15 Hz), 1.27 (9H, s).

Example 95

The title compound (10 mg, 32% yield, brown solid) was synthesized fromExample 94 Part B2 compound using the procedure employed in Example 94.[M+H]⁺=555.1; ¹H NMR (500 MHz, CDCl₃) δ 8.04 (2H, d, J=8.80 Hz), 7.68(2H, d, J=8.80 Hz), 7.49 (1H, s), 7.01 (1H, d, J=3.85 Hz), 4.15-4.22(4H, m), 3.37 (2H, d, J=21.44 Hz), 3.11 (3H, s), 1.40 (9H, s), 1.34 (6H,t, J=6.87 Hz).

Example 96

To a 0° C. solution of benzylacetone (0.54 mL, 3.6 mmol) and diethyloxalate (0.53 mL, 3.9 mmol) in dry EtOH (6 mL) was added NaOEt (0.31 mL,3.9 mmol). The reaction was slowly warmed to RT and stirred for 15 h atRT, then was diluted with EtOAc (20 mL) and washed with brine. Theorganic layer was dried (MgSO₄) and concentrated in vacuo to providePart A compound (0.65 g, 73% yield) as a yellow oil.

To a solution of the Part A compound (0.65 g, 2.6 mmol) in dry EtOH (5mL) was added O-methylhydroxylamine hydrochloride (0.31 g, 3.7 mmol) and3 A mol.sieves (2 g). The reaction was stirred at RT for 15 h, then wasfiltered and washed with EtOH. The combined filtrates were concentratedin vacuo, and the residue was partitioned between Et₂O and sat. aqueousNaHCO₃. The Et₂O layer was washed with water and brine, dried (MgSO₄)and concentrated in vacuo. The residue was chromatographed (SiO₂; 16 mingradient from 0% EtOAc/Hexanes to 100% EtOAc/Hexanes) to provide Part Bcompound (117 mg, 16%).

To a solution of Part B compound (117 mg, 0.42 mmol) in AcOH:EtOH (1.5mL) was added (4-(methylsulfonyl)phenyl)hydrazine (157 mg, 0.84 mmol).The reaction was stirred at 100° C. for 10 h, then was cooled to RT andconcentrated in vacuo. The residue was partitioned between EtOAc and0.2N aqueous HCl. The organic layer was washed with water and brine,dried (MgSO₄), filtered, and concentrated in vacuo. The residue waschromatographed (SiO₂; 22 min continuous gradient from 0% EtOAc/Hexanesto 100% EtOAc/Hexanes) to give Part C1 compound (20 mg, 12%) and Part C2compound (95 mg, 57%).

To a solution of Part C2 compound (28 mg, 0.07 mmol) in THF (1 mL) wasadded aqueous NaOH (0.3 mL of a 1 M solution, 0.30 mmol). The reactionwas stirred at RT for 15 h, then was diluted with EtOAc (4 mL) andacidified with 1N aqueous HCl (0.5 mL). The organic layer was washedwith brine, dried (MgSO₄) and concentrated in vacuo to give Part Dcompound (29 mg, 111% crude).

To a solution of the Part D compound (25.9 mg, 0.07 mmol) in DMF (1 mL)was added Example 13 Part E compound (35.0 mg, 0.14 mmol), EDCI (26.8mg, 0.14 mmol), HOBT (21.4 mg, 0.14 mmol) and Hunig's Base (0.037 mL,0.21 mmol). The reaction was stirred at RT for 2 days, then wasconcentrated in vacuo. The residue was purified directly by preparativeHPLC (Phenomenex Luna AXIA 30×100 mm column; detection at 220 nm; flowrate=40 mL/min; continuous gradient from 50% A to 100% B over 10 min,where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to providethe title compound (7 mg, 17% yield) as a grey solid. [M+H]⁺=603.0; ¹HNMR (500 MHz, CDCl₃) δ 8.04 (2H, d, J=8.80 Hz), 7.67 (2H, d, J=8.25 Hz),7.18-7.36 (5H, m), 7.14 (1H, br. s.), 6.90 (1H, s), 4.01-4.17 (4H, m),3.32 (2H, d, J=21.44 Hz), 3.00-3.15 (7H, m), 1.22-1.35 (6H, m).

Example 97

To a refluxing solution of sulfamide (6.09 mL; 102.0 mmol) in anhydrouspyridine (109.0 mL) was added dropwise 2-methylpropane-1,2-diamine (10.7mL; 102.0 mmol) over 30 min via syringe pump. The reaction mixture wasrefluxed for 16 h, then was cooled to RT and concentrated in vacuo. Theresidue was triturated with hexanes until the filtrate was nearlycolorless. The resulting solid was dried in vacuo to give Part Acompound (14.89 g, 97%) as a beige solid.

To a stirred solution of Ph₃P (26.0 g; 99.0 mmol) and Part A compound(14.89 g; 99.0 mmol) in anhydrous THF (300 mL) was added DIAD (19.3 mL;99.0 mmol) dropwise over 5 min under Ar. The reaction mixture wasstirred at RT for 16 h. The resulting off-white solid was filtered off,washed with anhydrous THF and anhydrous Et₂O, then dried in vacuo togive Part B compound (36.68 g, 90%) as an off-white solid.

To a suspension of Part B compound (1.4 g, 3.5 mmol) in DCM (6 mL) wasadded a solution of Example 26A compound (141 mg, 0.44 mmol) and(R)-(−)-3-hydroxytetrahydrofuran (0.08 mL, 1.0 mmol) in toluene (2 mL).The reaction was stirred at RT for 15 h, then was diluted with EtOAc,and washed with water and brine. The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo. The residue was chromatographed(SiO₂; 19 min gradient from 0% EtOAc/Hexanes to 100% EtOAc/0% Hexanes)to provide Part C compound (254 mg, 148% yield).

To a mixture of the Part C compound (254 mg, 0.65 mmol) in THF (2 mL)was added 1N aqueous NaOH (1 mL, 1.0 mmol). The reaction was stirred atRT for 15 h, then was diluted with EtOAc (6 mL) and acidified with 1Naqueous HCl (0.5 mL). The organic layer was washed with brine, dried(MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex Luna AXIA 30×100 mm column; detection at220 nm; flow rate=40 mL/min; continuous gradient from 70% A to 100% Bover 10 min, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give the Part D compound (90 mg, 54% yield over 2steps) as a colorless oil.

To a solution of Part D compound (43.0 mg, 0.11 mmol) in DMF (1 mL) wasadded Example 13 Part E compound (56.9 mg, 0.23 mmol), EDCI (43.6 mg,0.23 mmol), HOBT (34.8 mg, 0.23 mmol), and Hunig's Base (0.059 mL, 0.34mmol). The reaction was stirred at RT for 24 h and was purified directlyby preparative HPLC (Phenomenex Luna AXIA 30×100 mm column; detection at220 nm; flow rate=40 mL/min; continuous gradient from 70% A to 100% Bover 10 min, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to provide the title compound (36 mg, 52% yield) as awhite solid. [M+H]⁺=611.3; ¹H NMR (500 MHz, CDCl₃) δ 7.94 (2H, d, J=8.80Hz), 7.63 (1H, s), 7.49 (1H, s), 7.16 (2H, d, J=8.80 Hz), 7.07 (1H, d,J=3.85 Hz), 6.91 (1H, s), 5.22-5.33 (1H, m), 4.12-4.24 (4H, m),3.85-4.08 (4H, m), 3.37 (2H, d, J=20.89 Hz), 3.08 (3H, s), 2.08-2.41 (2H, m), 1.34 (6H, t, J=7.15 Hz).

Example 98

The title compound (10 mg, 16% yield, white solid) was prepared from(S)-(+)-3-hydroxytetrahydrofuran employing the same procedure asdescribed for the synthesis of Example 97 compound. [M+H]⁺=611.3; ¹H NMR(500 MHz, CDCl₃) δ 7.94 (2H, d, J=8.80 Hz), 7.57 (1H, s), 7.44 (1H, s),7.16 (2H, d, J=8.80 Hz), 7.00 (1H, d, J=3.30 Hz), 6.89 (1H, s),5.15-5.26 (1H, m), 4.06-4.19 (4H, m), 3.86-4.06 (4H, m), 3.32 (2H, d,J=20.89 Hz), 3.08 (3H, s), 2.06-2.39 (2H, m), 1.30 (6 H, t, J=7.15 Hz).

Example 99

The title compound (24 mg, 42% yield, white solid) was prepared from3-Methyl-3-Oxetane-methanol employing the same procedure as describedfor the synthesis of Example 97 compound. [M+H]⁺=625.3; ¹H NMR (500 MHz,CDCl₃) δ 7.94 (2H, d, J=8.80 Hz), 7.70 (1H, s), 7.51 (1H, s), 7.13-7.20(2H, m), 7.07 (1 H, d, J=3.30 Hz), 6.97 (1H, s), 4.70 (2H, d, J=6.05Hz), 4.51 (2H, d, J=6.05 Hz), 4.13-4.26 (6H, m), 3.98 (1H, s), 3.38 (2H,d, J=21.44 Hz), 3.08 (3H, s), 1.47 (3H, s), 1.34 (6H, t, J=7.15 Hz).

Example 100

To a solution of1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(61 mg, 0.213 mmol) [see WO 1998/57937] in DMF (1 ml), was added Example13 Part E compound (107 mg, 0.426 mmol), EDC (82 mg, 0.426 mmol), HOBT(65.3 mg, 0.426 mmol), and DIPEA (0.111 ml, 0.639 mmol). The reactionmixture was stirred at RT for 4 days. The reaction mixture was purifieddirectly by preparative HPLC (Phenomenex Luna AXIA 30×100 mm column;detection at 220 nm; flow rate=40 mL/min; continuous gradient from 50% Bto 100% B over 10 min, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to provide the title compound (13 mg, 12% yield) as a greysolid. [M+H]⁺=519.0; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (1H, s), 7.33-7.46(2H, m), 6.91-7.02 (2H, m), 6.80 (1H, d, J=3.52 Hz), 3.99-4.15 (4H, m),3.86 (3H, s), 3.51 (2H, d, J=21.53 Hz), 1.26 (6H, t, J=7.03 Hz).

Example 101

To a solution of methyl 3,5-dihydroxybenzoate (2.7 g, 16.06 mmol) inCH₃CN (35 mL) was added K₂CO₃ (2.70 g, 19.54 mmol), followed by slowaddition of 2-bromopropane (1.975 g, 16.06 mmol). The reaction mixturewas heated to 80° C. for 3 days. The reaction mixture was diluted withwater and extracted with EtOAc (3×). The combined organic layer waswashed H₂O and brine, dried (MgSO₄), filtered, and concentrated invacuo. The residue was purified by column chromatography (SiO₂;continuous gradient 15% EtOAc/Hex to 60% EtOAc/Hexane) to give Part Acompound (1.22 g, 36% yield) as yellow solid. [M+H]⁺=211.0; ¹H NMR (400MHz, CDCl₃) δ 1.33 (d, J=6.15 Hz, 6H), 3.89 (s, 3H), 4.51-4.62 (m, 1 H),5.21 (s, 1H), 6.59 (t, J=2.42 Hz, 1H), 7.08-7.12 (m, 1H), 7.13-7.17 (m,1H).

To a solution of Part A compound (300 mg, 1.427 mmol) and tert-butyl4-hydroxypiperidine-1-carboxylate (1.15 g, 5.7 mmol) in toluene (2 mL)was added a suspension of Example 97B compound (2.34 g, 5.7 mmol) in DCM(2 mL). The reaction mixture was stirred at RT for 3 h, then wasconcentrated in vacuo. The residue was chromatographed (SiO₂; continuousgradient from 10% EtOAc/Hex to 60% EtOAc/Hexane) to give Part B compound(490 mg, 87%) as a light yellow solid. [M+H]⁺=294.0; ¹H NMR (500 MHz,CDCl₃) δ 1.32 (d, J=6.05 Hz, 6H), 1.45 (s, 9 H), 1.66-1.78 (m, 2H),1.85-1.96 (m, 2H), 3.26-3.38 (m, 3H), 3.62-3.72 (m, 3 H), 3.86-3.90 (m,3H), 4.44-4.51 (m, 1H), 4.52-4.62 (m, 1H), 6.61 (t, J=2.20 Hz, 1H),7.10-7.19 (m, 2H).

To a 0° C. solution of Part B compound (490 mg, 1.245 mmol) in THF/water(1/1, 4 mL) was added LiOH.H₂O (209 mg, 4.98 mmol). The mixture wasstirred at RT for 18 h, then was diluted with EtOAc and acidified with1N aqueous HCl to pH-4-5. The aqueous layer was extracted with EtOAc(2×). The combined organic extracts were washed with 1N aqueous HCl,H₂O, and brine, dried (MgSO₄) and concentrated in vacuo to provide PartC compound (440 mg, 93% yield) as a white solid. [M+H]⁺=561.1.

To a solution of Part C compound (200 mg, 0.527 mmol) and Example 13Part E compound (132 mg, 0.527 mmol) (buffered with DIEA) in DCM/DMF(1/1) were successively added HOAT (201 mg, 1.476 mmol), EDCI (202 mg,1.054 mmol), and DIEA (641 μL, 3.69 mmol). The reaction mixture wasstirred at RT for 18 h, then was diluted with DCM. The organic layer waswashed with water (2×) and brine, dried (MgSO₄) and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient 0%DCM/MeOH to 5% DCM/MeOH) to give the title compound (140 mg, 43% yield)as a white solid. [M+H]⁺=612; ¹H NMR (500 MHz, CDCl₃) δ 1.26 (t, J=7.15Hz, 6H), 1.33 (d, J=6.05 Hz, 6H), 1.45 (s, 9H), 1.63 (s, 2H), 1.67-1.80(m, 2H), 1.92 (dd, J=12.65, 3.85 Hz, 2H), 3.21-3.39 (m, 4H), 3.63-3.76(m, 2H), 4.00-4.14 (m, 4H), 4.44-4.53 (m, 1H), 4.53-4.62 (m, 1H), 6.63(t, J=2.20 Hz, 1H), 6.84 (d, J=3.85 Hz, 1H), 8.00 (s, 1H).

Example 102

To a solution of Example 101 compound (15 mg, 0.025 mmol) in DCM (0.5mL) was added TFA (0.15 mL). The reaction mixture was stirred at RT for2 h, then was concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex AXIA 5 u C18 30×100 mm column; detection at220 nm; flow rate=40 mL/min; continuous gradient from 35% B to 100% Bover 10 min, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) give the title compound (11 mg, 85% yield) as a whitesolid. [M+H]⁺=512; ¹H NMR (500 MHz, CDCl₃) δ 1.29 (t, J=7.15 Hz, 6H),1.33 (d, J=5.50 Hz, 6H), 2.08-2.16 (m, 2H), 2.16-2.26 (m, 2H), 3.22 (d,J=9.90 Hz, 2H), 3.30 (d, J=21.44 Hz, 2H), 3.35 (d, J=7.70 Hz, 2H),4.02-4.17 (m, 4H), 4.60-4.73 (m, 1H), 4.82 (s, 1H), 6.69 (t, J=2.20 Hz,1H), 6.96 (d, J=3.30 Hz, 1H), 7.36 (d, J=8.80 Hz, 2H), 9.37 (s, 1H),9.47 (s, 1H).

Example 103

To a solution of Example 102 compound (30 mg, 0.059 mmol) in THF (1 mL)and sat. aqueous NaHCO₃ (1 mL) was added methyl chloroformate (6.77 μL,0.088 mmol). The reaction mixture was stirred at RT for 18 h, then wasdiluted with EtOAc. The aqueous layer was extracted with EtOAc (2×), andthe combined organic extracts were concentrated in vacuo. The residuewas purified by preparative HPLC (Phenomenex AXIA 5 u C18 30×100 mmcolumn; detection at 220 nm; flow rate=40 mL/min; continuous gradientfrom 35% B to 100% B over 10 min, where A=90:10:0.1 H₂O:MeOH:TFA andB=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (16 mg, 48% yield)as a white solid. [M+H]⁺=570.3; ¹H NMR (500 MHz, CDCl₃) δ 1.30 (t,J=7.15 Hz, 6H), 1.33 (d, J=6.05 Hz, 6H), 1.76 (s, 2H), 1.91 (s, 2H),3.31 (d, J=20.89 Hz, 2H), 3.31 (d, J=20.89 Hz, 2H), 3.44 (s, 2H), 3.66(d, J=5.50 Hz, 2H), 3.69 (s, 3H), 4.10-4.17 (m, 4H), 4.64-4.75 (m, 2H),6.69 (t, J=2.20 Hz, 1H), 7.01 (d, J=3.30 Hz, 1H), 7.33 (dd, J=4.67, 1.92Hz, 2H).

Example 104

To a solution of Example 102 compound (30 mg, 0.059 mmol) in DCM (1 mL)was added pyridine (0.1 mL) and acetyl chloride (6.90 mg, 0.088 mmol).The reaction was stirred at RT for 18 h, then was diluted with EtOAc.The aqueous layer was extracted with EtOAc (2×), and the combinedorganic extracts were concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex AXIA 5 u C18 30×100 mm column; detection at220 nm; flow rate=40 mL/min; continuous gradient from 35% B to 100% Bover 10 min, where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (22 mg, 68% yield) as a whitesolid. [M+H]⁺=554.4; ¹H NMR (500 MHz, CDCl₃) δ 1.34 (t, J=7.15 Hz, 6H),1.36 (d, J=6.05 Hz, 6H), 1.79-2.04 (m, 4H), 2.17 (s, 3H), 3.36 (d,J=21.44 Hz, 2H), 3.43-3.54 (m, 1H), 3.63-3.86 (m, 3H), 4.12-4.24 (m,4H), 4.68-4.86 (m, 2H), 6.73 (s, 1H), 7.06 (d, J=3.30 Hz, 2H), 7.39 (s,2H).

Example 105

A solution of Example 102 compound (50 mg, 0.098 mmol) and Et₃N (10 mg,0.098 mmol) in DCM (0.5 mL) was added to a solution of methanesulfonylchloride (11.20 mg, 0.098 mmol) in DCM (0.5 mL). The reaction wasstirred at RT for 18 h, then was diluted with EtOAc. The aqueous layerwas extracted with EtOAc (2×), and the combined organic extracts wereconcentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex AXIA 5 μm C18 30×100 mm column; detection at 220 nm; flowrate=40 mL/min; continuous gradient from 35% B to 100% B over 10 min,where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give thetitle compound (19.5 mg, 34% yield) as a colorless oil. [M+H]⁺=590.3; ¹HNMR (500 MHz, CDCl₃) δ 1.28-1.38 (m, 12H), 1.93-2.10 (m, 4 H), 2.97 (s,3H), 3.29-3.40 (m, 6H), 4.12-4.22 (m, 4H), 4.68-4.75 (m, 2H), 6.70 (t,J=2.20 Hz, 1H), 7.03 (d, J=3.85 Hz, 1H), 7.337 (d, 1.10 Hz, 2H).

Example 106

To a solution of Example 26 Part C compound (25.0 mg; 0.066 mmol),Example 18 Part D compound (20.9 mg; 0.079 mmol), and HOAt (10.3 mg;0.076 mmol) in DMF (0.25 mL) were successively added DIPEA (13.2 μL;0.076 mmol) and EDAC (14.6 mg; 0.076 mmol). The reaction was stirred atRT for 20 h, then was partitioned between EtOAc (4 mL) and H₂O (3 mL).The organic layer was washed with 0.5 N aqueous HCl (3 mL), sat. aqueousNaHCO₃ (3 mL), and brine (3 mL), dried (MgSO₄) and concentrated invacuo. The residue was purified by preparative HPLC(YMC reverse phaseODS-A-5 μm 20×100 mm column; flow rate=20 mL/min, 15 to 100% solvent Bover 10 min, hold to 14 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA andsolvent B=90:10:0.1 MeOH:H₂O:TFA) to give the title compound (22.0 mg;54%) as a light yellow solid. [M+H]⁺=627.1; ¹H NMR (400 MHz, CDCl₃): δ1.34 (m, 9H), 2.19 (m, 2H), 3.07 (m, 5H), 3.41 (s, 3H), 3.57 (m, 2H),4.12 (m, 4H), 4.89 (m, 1H), 6.81 (s, 1H), 6.94 (s, 1H), 7.15 (d, 2H),7.44 (s, 1H), 7.69 (s, 1H), 7.92 (d, 2H).

Example 107

The title compound (20 mg, 65% yield, white solid) was prepared fromracemic-ethyl (3-amino-1H-pyrazol-1-yl)methyl(methyl) phosphinateemploying the same general sequence as used to prepare Example 58.[M+H]⁺=566.3; ¹H NMR (400 MHz, CD₃OD): δ 1.33 (d, J=6.6 Hz, 3H), 1.34(t, J=6.6 Hz, 3H), 1.57 (d, J=14.3 Hz, 3H), 3.01 (s, 3H), 3.42 (s, 3H),3.53-3.63 (m, 2H), 4.08-4.21 (m, 2H), 4.52 (dd, J=2.4, 6.0 Hz, 2H), 4.71(m, 1H), 6.86 (d, J=2.2 Hz, 1H), 7.03 (s, 1H), 7.14 (d, J=8.8 Hz, 2H),7.24 (s, 1H), 7.39 (s, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.91 (d, J=8.8 Hz,2H).

Example 108

To a stirred 10° C. solution of chloromethyl(methyl)phosphinic chloride(2 g, 13.61 mmol) in Et₂O (10 mL) was added dropwise MeMgBr (4.54 mL ofa 3 M solution in Et₂O, 13.61 mmol). The reaction turned cloudy andgummy, then was slowly warmed to RT for 1 h. Volatiles were removed invacuo and the residue was carefully quenched with sat. aqueous NaHCO₃and extracted with CHCl₃ (4×). The combined organic extracts were dried(MgSO₄) and concentrated in vacuo. To the resulting clear oil was addedhexanes (50 mL); a white precipitate formed. The precipitated wasfiltered to collect the white solid (crystalline, fine needles) as PartA compound (360 mg, 21%).

To a stirred solution of 3-nitro-1H-pyrazole (45 mg, 0.398 mmol) in DMF(2 mL) was added K₂CO₃ (70 mg, 0.506 mmol) and Part A compound (70 mg,0.553 mmol). The reaction was stirred at 75° C. for 16 h, then wascooled to RT and partitioned between EtOAc and saturated aqueous NH₄Cl.The aqueous layer was extracted with CHCl₃ (10×), and the combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo to givePart B compound (50 mg, 62% yield) as a white solid.

To a stirred solution of Part B compound (50 mg, 0.246 mmol) in MeOH (3mL) was added Pd/C (26.2 mg, 0.025 mmol). The reaction was stirred underan atmosphere of H₂ (balloon) for 1 h, then was filtered through Celite®and concentrated in vacuo to give Part C compound (35 mg, 82%) as alight yellow oil.

To a stirred solution of Example 26 Part C acid (77 mg, 0.202 mmol) inDMF (2 mL) was added HOBT (55.0 mg, 0.404 mmol), EDC (77 mg, 0.404mmol), and Hunig's Base (0.106 mL, 0.606 mmol). The reaction was stirredat RT for 30 min, after which Part C compound (35 mg, 0.202 mmol) wasadded. The reaction was stirred at RT for 20 h, then was partitionedbetween 1N aqueous HCl and CH₂Cl₂. The organic phase was washed withsat. aqueous NH₄Cl and brine, dried (MgSO₄) and concentrated in vacuo.The residue was purified by preparative HPLC (Luna 5 μm 21.2×100 mmcolumn; flow rate=20 mL/min, 0 to 100% solvent B over 12 min, hold to 15min, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to give the title compound (59 mg, 55% yield) as a whitesolid. [M+H]⁺=536.3; ¹H NMR (400 MHz, CD₃OD): δ 1.31 (d, J=6.9 Hz, 3H),1.64 (d, J=13.2 Hz, 6H), 2.99 (s, 3H), 3.40 (s, 3H), 3.48-3.61 (m, 2H),4.60 (d, J=6.6 Hz, 2H), 4.68 (m, 1H), 6.84 (s, 1H), 6.96 (d, J=2.2 Hz,1H), 7.11 (d, J=8.8 Hz, 2H), 7.21 (s, 1H), 7.34 (s, 1H), 7.52 (d, J=2.2Hz, 1H), 7.88 (d, J=8.8 Hz, 2H).

Example 109

To a solution of Example 101 Part A compound (300 mg, 1.427 mmol) and(R) tert-butyl-3-hydroxypyrrolidine-carboxylate (534m g, 2.85 mmol) intoluene (2 mL) was added a suspension of Example 97 Part B compound(1.17 g, 2.85 mmol) in DCM (2 mL). The reaction mixture was stirred atRT for 3 h, then was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient 10% EtOAc/Hex to 60%EtOAc/Hexane) to give Part A compound (500 mg, 92%) as a white solid.[M+H]⁺=402; ¹H NMR (400 MHz, CDCl₃) δ 1.25 (d, J=6.15 Hz, 6 H), 1.39 (d,J=7.47 Hz, 9H), 1.95-2.22 (m, 2H), 3.25-3.46 (m, 4H), 3.47-3.58 (m, 1H),3.82 (s, 3H), 4.61-4.73 (m, 1H), 5.07 (s, 1H), 6.76 (t, J=2.42 Hz, 1H),7.00 (s, 1H), 7.03 (s, 1H).

To a 0° C. solution of Part A compound (500 mg, 1.318 mmol) in THF/water(1/1, 4 mL) was added LiOH.H₂O (270 mg, 6.59 mmol). The mixture wasstirred at RT for 18 h, then was diluted with EtOAc and acidified with1N aqueous HCl to pH-4-5. The aqueous layer was extracted with EtOAc(2×). The combined organic extracts were washed with 1N aqueous HCl,H₂O, and brine, dried (MgSO₄) and concentrated in vacuo to provide PartB compound (480 mg, 100% yield) as a white solid. MS [M−H]⁻=364.4.

To a solution of Part B compound (200 mg, 0.547 mmol) and Example 13Part E compound (137 mg, 0.547 mmol) in DCM/DMF (1/1; buffered withDIEA) were successively added HOAT (208 mg, 1.53 mmol), EDCI (210 mg,1.094 mmol), and DIPEA (665 μL, 3.83 mmol). The reaction mixture wasstirred at RT for 18 h, then was diluted with DCM. The organic phase waswashed with water (2×) and brine, dried (MgSO₄), and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from0% DCM/MeOH to 5% DCM/MeOH) to give the title compound (160 mg, 49%yield) as a white solid. [M+H]⁺=598.3; ¹H NMR (500 MHz, CDCl₃) δ 1.26(t, J=7.15 Hz, 6H), 1.33 (d, J=6.05 Hz, 6H,) 1.45 (s, 9H), 1.64 (s, 2H),2.02-2.24 (m, 2H), 3.28 (d, J=21.44 Hz, 2H), 3.41-3.70 (m, 4H),4.01-4.16 (m, 4H), 4.51-4.63 (m, 1H), 6.98 (s, 1H), 7.03 (s, 1H), 9.71(s, 1H).

Example 110

The title compound (10.4 mg, 71% yield, white solid) was prepared fromExample 109 compound employing the same general sequence as used toprepare Example 102. [M+H]⁺=498.0; ¹H NMR (500 MHz, CDCl₃) δ 1.24-1.29(m, 6H), 1.32 (d, J=6.05 Hz, 6H), 2.22-2.44 (m, 2H), 3.26 (d, J=21.44Hz, 2H), 4.01-4.16 (m, 4H), 4.58-4.70 (m, 1H), 5.24 (s, 1H), 6.66 (s,1H), 6.93 (d, J=3.30 Hz, 1H), 7.29 (s, 1H), 7.33 (s, 1H), 9.81 (s, 1H),10.30 (s, 1H).

Example 111

The title compound (22.5 mg, 68% yield, colorless oil) was prepared fromExample 110 compound employing the same general sequence as used toprepare Example 103. [M+H]⁺=556.3; ¹H NMR (500 MHz, CDCl₃) δ 1.29-1.35(m, 12 H), 2.13 (s, 1H), 2.20 (s, 1H), 3.35 (d, J=21.44 Hz, 2H),3.48-3.65 (m, J=28.04 Hz, 4H), 3.70 (d, J=11.55 Hz, 4H), 4.13-4.20 (m,4H), 4.64-4.74 (m, 1H), 5.14 (s, 1 H), 6.66 (t, J=1.92 Hz, 1H), 7.03 (d,J=3.30 Hz, 1H), 7.31-7.41 (m, 2H).

Example 112

The title compound (24 mg, 74% yield, light yellow oil) was preparedfrom Example 110 compound employing the same general sequence as used toprepare Example 104. [M+H]⁺=540.4; ¹H NMR (500 MHz, CDCl₃) δ 1.32-1.35(m, 6H), 1.35-1.39 (m, 6H), 2.09-2.20 (m, J=23.09 Hz, 3H), 2.21-2.43 (m,2H), 3.37 (d, J=21.44 Hz, 2H), 3.55-3.92 (m, 4H), 4.13-4.24 (m, 4H),4.66-4.76 (m, 1 H), 5.19-5.30 (m, 1H), 6.67-6.72 (m, 1H), 7.07 (d,J=3.85 Hz, 1H), 7.39 (s, 1H), 7.40-7.44 (m, 1H).

Example 113

The title compound (28 mg, 43% yield, white solid) was prepared fromExample 110 compound employing the same general sequence as used toprepare Example 105. [M+H]⁺=576.3; ¹H NMR (500 MHz, CDCl₃) δ 1.32 (t,J=7.15 Hz, 6 H), 1.35 (dd, J=6.05, 1.10 Hz, 6H), 2.17-2.37 (m, 2H), 2.83(s, 3H), 3.34 (d, J=20.89 Hz, 2H), 3.42-3.52 (m, 1H), 3.54-3.71 (m, 3H),4.11-4.23 (m, 4H), 4.65-4.77 (m, 1H), 5.16 (s, 1H), 6.64 (t, J=2.20 Hz,1H), 7.35 (s, 1H), 7.41 (d, J=3.30 Hz, 1H).

Example 114

The title compound (176 mg, 32% yield, white solid) was prepared from(S) tert-butyl-3-hydroxypyrrolidine-carboxylate employing the samegeneral sequence as used to prepare Example 109. [M+H]⁺=598.4; ¹H NMR(500 MHz, CDCl₃) δ 1.26 (t, J=7.15 Hz, 6H), 1.34 (d, J=5.50 Hz, 6H),1.45 (s, 9H), 1.63 (s, 2 H), 2.00-2.27 (m, 2H), 3.28 (d, J=20.89 Hz,2H), 3.39-3.70 (m, 4H), 3.99-4.18 (m, 4H), 4.50-4.66 (m, 1H), 4.91 (s,1H), 6.59 (s, 1H), 6.84 (s, 1H), 6.96-7.10 (m, 2H).

Example 115

The title compound (13.4 mg, 67% yield, white solid) was prepared fromExample 114 compound employing the same general sequence as used toprepare Example 110. [M+H]⁺=498.3; ¹H NMR (500 MHz, CDCl₃) δ 1.22-1.28(m, 6H), 1.32 (d, J=6.05 Hz, 6H), 2.24-2.40 (m, 2H), 3.24 (d, J=21.44Hz, 2H), 3.41-3.69 (m, 4H), 3.97-4.13 (m, 4H), 4.56-4.69 (m, 1H), 5.22(s, 1H), 6.64 (t, J=2.20 Hz, 1H), 6.89 (d, J=3.85 Hz, 1H), 7.28 (s, 1H),7.32 (s, 1H).

Example 116

The title compound (32.5 mg, 83% yield, colorless oil) was prepared fromExample 115 compound employing the same general sequence as used toprepare Example 111. [M+H]⁺=554; ¹H NMR (500 MHz, CDCl₃) δ 1.29-1.32 (m,6H), 1.33 (d, J=5.50 Hz, 6H), 2.05-2.28 (m, 2H), 3.35 (d, J=21.44 Hz,2H), 3.45-3.74 (m, 7H), 4.11-4.22 (m, 4H), 4.65-4.74 (m, 1H), 5.14 (s,1H), 6.66 (t, J=1.92 Hz, 1H), 7.03 (d, J=3.30 Hz, 1H), 7.33 (s, 1H),7.38 (s, 1H).

Example 117

The title compound (28.5 mg, 75% yield, light yellow oil) was preparedfrom Example 115 compound employing the same general sequence as used toprepare Example 112. [M+H]⁺=540.2; ¹H NMR (500 MHz, CDCl₃) δ 1.29-1.32(m, 6H), 1.32-1.36 (m, 6H), 2.12 (d, J=23.09 Hz, 3H), 2.19-2.39 (m, 2H),3.34 (d, J=21.44 Hz, 2H), 3.55-3.88 (m, 4H), 4.11-4.21 (m, 4H),4.64-4.73 (m, 1H), 5.17-5.28 (m, 1H), 6.64-6.69 (m, 1H), 7.04 (d, J=2.75Hz, 1H), 7.35 (d, J=1.10 Hz, 1H), 7.39 (d, J=9.35 Hz, 1H).

Example 118

The title compound (12 mg, 30% yield, light yellow oil) was preparedfrom Example 115 compound employing the same general sequence as used toprepare Example 113. [M+H]⁺=576.2; ¹H NMR (500 MHz, CDCl₃) δ 1.31-1.34(m, 6H), 1.36 (d, J=6.05 Hz, 6H), 2.08-2.39 (m, 2H), 2.85 (s, 3H), 3.37(d, J=21.44 Hz, 2H), 3.44-3.54 (m, 1H), 3.56-3.72 (m, 3H), 4.13-4.25 (m,4H), 4.68-4.80 (m, 1H), 5.18 (s, 1H), 6.66 (s, 1H), 7.07 (d, J=3.30 Hz,1H), 7.37 (s, 1 H), 7.43 (s, 1H).

Example 119

To a RT solution of Example 101 Part A ester (94.7 mg, 0.450 mmol) inMeCN (2.2 mL) under Ar was added 1,4,7,10,13,16-hexaoxacyclooctadecane(16 mg, 0.061 mmol), K₂CO₃ (178 mg, 1.288 mmol), and bromomethyl phenylsulfone (120 mg, 0.510 mmol). The mixture was heated at 70° C. for 6 h,then at 90° C. for 4 h. DMF (1 mL) was added, and the reaction washeated at 115° C. for 24 h. After 24 hours, more bromomethyl phenylsulphone (90 mg, 0.382 mmol) was added, and the reaction was stirred at115° C. for 3 days, then cooled to RT and stirred at RT for 2 days. Thedark brown mixture was partitioned between EtOAc and saturated aqueousNaHCO₃. The organic layer was washed with saturated aqueous NaHCO₃,water, and brine, dried (Na₂SO₄), and concentrated in vacuo. The residuewas chromatographed (SiO₂, 12 g, eluting from 0-10%, then 35%EtOAc:hexanes, finally flushing with 100% EtOAc) to give impure Part Acompound (70 mg) as an oil. The residue was further purified bypreparative HPLC (Phenomenex AXIA Luna 5 u, 75×30 mm, detection at 220nm; flow rate=40 mL/min; continuous gradient from 40% A to 100% B over15 min+3 min hold time at 100% B, where A=90:10:0.1 H₂O:CH₃CN:TFA andB=90:10:0.1 CH₃CN:H₂O:TFA) to give Part A compound (9.2 mg, 5.5%) as anoily solid.

To a RT solution of Part A compound (9 mg, 0.025 mmol) in THF (0.2 mL)and MeOH (0.1 mL) under Ar was added 4N aqueous LiOH (0.062 mL, 0.247mmol). The reaction was stirred at RT for 8 h, then was stored at −20°C. for 18 h. After warming to RT and diluting with EtOAc, volatiles wereremoved in vacuo to give a colorless solid. The residue was suspended inwater, brought to pH 1 with 1N aqueous HCl (0.3 mL), and the aqueouslayer was extracted with EtOAc (2×). The combined organic extracts werewashed with brine, dried (Na₂SO₄) and concentrated in vacuo to give PartB compound (10.6 mg, >100% recovery) as a colorless solid.

To Part B acid (8.76 mg, 0.025 mmol) was added a RT solution of Example13 Part E amine (21 mg, 0.084 mmol) in CH₂Cl₂ (0.800 mL) under Ar. Tothe resulting mixture was added iPr₂NEt (0.030 mL, 0.175 mmol) followedby addition of HATU (14.2 mg, 0.037 mmol). The solution was stirred atRT for 18 h, after which another portion of Example 13 Part E amine (15mg, 0.06 mmol) was added, and stirring was continued at RT for 18 h. Thereaction was partitioned between EtOAc and saturated aqueous NaHCO₃after stirring for 15 min. The organic layer was washed with saturatedaqueous NaHCO₃ and brine, dried (Na₂SO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC (Phenomenex Luna 5 μm 21.2×100mm column, detection at 220 nm; flow rate=20 mL/min; continuous gradientfrom 60% A to 100% B over 10 min+2 min hold time at 100% B, whereA=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA). This materialwas further purified by preparative HPLC (Phenomenex Luna, 5 micron21.2×100 mm, detection at 220 nm; flow rate=20 mL/min; continuousgradient from 35% A to 100% B over 10 min+2 min hold time at 100% B,where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA). Thematerial was finally purified by passing through a MeOH-treatedcartridge of Polymer Lab StratoSpheres™ SPE PL-HCO₃ MP SPE resin (500mg), washing well with MeOH. The filtrate was concentrated in vacuo andthe resulting solid dissolved in CH₂Cl₂/MeOH, filtered, and concentratedin vacuo to give the title compound (5 mg, 34%) as a tan solid.[M+H]⁺=583.3; ¹H NMR (400 MHz, CDCl₃) δ 1.27 (t, J=6.87 Hz, 6H), 1.33(d, J=6.05 Hz, 6H), 3.33 (d, J=20.89 Hz, 2 H), 4.07 (td, J=7.15, 4.40Hz, 4H), 4.55-4.58 (m, 1H), 5.11 (s, 2H), 6.67 (s, 1H), 6.83 (d, J=3.30Hz, 1H), 7.08 (s, 1H), 7.16 (s, 1H), 7.59 (t, J=7.70 Hz, 2H), 7.69 (t,J=7.15 Hz, 1H), 7.97 (d, J=7.15 Hz, 2H).

Example 120

To a 0° C. solution of Example 101 Part A compound (183.9 mg, 0.875mmol) in DMPU (4.5 mL) under Ar was added NaH (35.0 mg of a 60%dispersion in oil, 0.875 mmol). To the resulting solution was added2-bromoacetophenone (174 mg, 0.875 mmol). The reaction was stirred at 0°C. for several min and then warmed to RT and stirred at RT for 1.5 h.More 2-bromoacetophenone (39 mg, 0.19 mmol) was added, and the reactionwas stirred at RT for 1 h. The reaction was quenched with water andEtOAc was added. The organic layer was washed with water (2×) and brine(1×), dried (Na₂SO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂, 12 g, eluting from 0-5% EtOAc:CH₂Cl₂, thenflushing with 90% EtOAc) to give Part A compound (274 mg, 95%) as ayellow oil.

To a RT solution of Part A compound (101.4 mg, 0.309 mmol) in TF (2.4mL) under Ar was added water (0.6 mL), followed by LiOH.H₂O (54.7 mg,1.304 mmol). The reaction was stirred at RT for 18 h, and aqueous LiOH(0.2 mL of a 4 M solution, 0.8 mmol) was added. After stirring for 5.5h, MeOH (0.5 mL) was added; stirring was continued at RT for 2.5 h andthe reaction was stored at −20° C. for 18 h. After warming to RT, thereaction was stirred for another 4.5 h. Volatiles were removed in vacuoto give an orange aqueous mixture, which was acidified with 1N aqueousHCl (1.9 mL), then was partitioned between EtOAc and water. The organiclayer was washed with water and brine, dried (Na₂SO₄) and concentratedin vacuo to give crude Part B compound (88 mg, 49%) as a yellow oil.

To a RT solution of Part B acid (<88 mg, <0.280 mmol) in CH₂Cl₂ (1.4 mL)under Ar were successively added HATU (166 mg, 0.437 mmol), DIPEA (0.34mL, 1.952 mmol) and a solution of Example 13 Part E compound (162 mg,0.445 mmol) in CH₂Cl₂ (0.6 mL). The reaction was stirred at RT for 65 h,then was partitioned between EtOAc and sat. aqueous NaHCO₃. The organiclayer was washed with saturated aqueous NaHCO₃ and brine, dried (Na₂SO₄)and concentrated in vacuo. The residue was purified by preparativeHPLC(YMC ODS S5 30×250 mm column, detection at 220 nm; flow rate=25mL/min; continuous gradient from 50% A to 100% B over 20 min+5 min holdtime at 100% B, where A=90:10:0.1 H₂O:CH₃CN:TFA and B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (33 mg, 22%) as a gummy,yellow solid. [M+H]⁺=545.3; ¹H NMR (400 MHz, CD₃OD): δ 1.28 (t, J=7.15Hz, 6H), 1.34 (d, J=6.05 Hz, 6H), 3.36 (d, J=16.49 Hz, 2 H), 4.04-4.14(m, 4H), 4.64-4.86 (m, 1H), 5.55 (s, 2H), 6.78-6.80 (m, 1H), 6.95-6.97(m, 1H), 7.18-7.21 (m, 2H), 7.50-7.58 (t, J=7.97 Hz 2H), 7.65-7.70 (m,1H), 8.07 (d, J=7.15 Hz, 2H).

Example 121

To a 0° C. solution of Example 120 ketone (28 mg, 0.051 mmol) in MeOH (1mL) under Ar was added NaBH₄ (10 mg, 0.264 mmol). After 15 minutes, thereaction was allowed to warm to RT and stirred at RT for 4 h. Themixture was stored at −20° C. for 18 h, then was treated with pH 3aqueous phosphate buffer, allowed to warm to RT and stirred at RT for 40min. Volatiles were removed in vacuo, and the resulting aqueous mixturewas partitioned between water, phosphate buffer and EtOAc. The organiclayer was washed with water and brine, dried (Na₂SO₄) and concentratedin vacuo. The residue was purified by preparative HPLC (Phenomenex AXIALuna 5 μm 75×30 mm, detection at 220 nm; flow rate=40 mL/min; continuousgradient from 40% A to 100% B over 15 min+3 min hold time at 100% B,where A=90:10:0.1 H₂O:CH₃CN:TFA and B=90:10:0.1 CH₃CN:H₂O:TFA) to givetwo fractions containing the desired title compound. Both fractions werepassed through a MeOH-treated cartridge of Polymer Lab StratoSpheres™SPE PL-HCO3 MP SPE resin (500 mg), washing well with MeOH. The filtrateswere concentrated in vacuo, and the resulting solids were dissolved inCH₂Cl₂/MeOH, and concentrated in vacuo to give the title compound (17mg, 60%) as a tan solid. [M+H]⁺=549.2; [M−H]⁻=547.2; ¹H NMR (400 MHz,CD₃OD): δ 1.28 (t, J=6.87 Hz, 6H), 1.33 (d, J=6.05 Hz, 6H), 3.35 (d,J=20.89 Hz, 2H), 4.05-4.17 (m, 6H), 4.63-4.69 (m, 1H), 5.02-5.07 (m,1H), 6.71-6.73 (m, 1H), 6.95 (d, J=3.85 Hz, 1H), 7.13-7.15 (m, 2H),7.27-7.30 (m, 1H), 7.37 (t, J=7.42 Hz, 2 H), 7.48 (d, J=7.15 Hz, 2H).

Example 122

To a RT solution of Example 120 Part A compound (53.7 mg, 0.164 mmol) inCH₂Cl₂ (0.5 mL) under Ar was added bis-(2-methoxyethyl)aminosulfurtrifluoride (0.3 mL, 1.627 mmol). The orange solution was stirred at RTunder Ar for 18 h, then was diluted with CH₂Cl₂ and added carefully to astirred mixture of ice and sat. aqueous NaHCO₃. The mixture was stirredfor 1 h, then was partitioned between CH₂Cl₂ and sat. aqueous NaHCO₃.The aqueous layer was extracted CH₂Cl₂ (2×), and the combined organicextracts were washed with brine, dried (Na₂SO₄) and concentrated invacuo to give crude Part A ester (54.4 mg, 95% recovered) as a yellowoil.

To a RT solution of Part A ester (54.4 mg, 0.155 mmol) in THF (0.8 mL)and MeOH (0.4 mL) under Ar was added 4N aqueous LiOH (0.35 mL, 1.4mmol). The reaction was stirred at RT for 6 h, and the volatiles wereremoved in vacuo. The orange aqueous mixture was acidified with 1Naqueous HCl (1.5 mL). The resulting mixture was partitioned betweenwater and EtOAc. The organic layer was washed with water and brine,dried (Na₂SO₄) and concentrated in vacuo to give Part B compound (46.7mg, 89% recovered) as a yellow oily solid.

To a RT solution of Part B compound (21.2 mg, 0.063 mmol) in CH₂Cl₂ (0.6mL) under Ar were successively added HATU (34 mg, 0.089 mmol), iPr₂NEt(35 μL, 0.201 mmol), and a solution of Example 32 Part A amine (20.6 mg,0.088 mmol) in CH₂Cl₂ (0.3 mL). The reaction was stirred for 41 h at RT,then was diluted with CH₂Cl₂, saturated aqueous NaHCO₃, and EtOAc, thenstirred for 15 min and partitioned between EtOAc and aqueous NaHCO₃. Theaqueous layer was extracted with EtOAc (2×), and the combined organicextracts were washed with brine, dried (Na₂SO₄), and concentrated invacuo. The residue was purified by preparative HPLC (YMC ODS 30×250 mmcolumn, detection at 220 nm; flow rate=25 mL/min; continuous gradientfrom 50% A to 100% B over 25 min+7 min hold time at 100% B, whereA=90:10:0.1 H₂O:CH₃CN:TFA and B=90:10:0.1 CH₃CN:H₂O:TFA) to giveslightly impure title compound (34.3 mg) as a colorless oil. The residuewas purified further by preparative HPLC (Phenomenex AXIA 5 micron C1830×100 mm column, detection at 220 nm; flow rate=40 mL/min; continuousgradient from 60% A to 100% B over 10 min+5 min hold time at 100% B,where A=90:10:0.1 H₂O:MeOH:TFA and B=90:10:0.1 MeOH:H₂O:TFA) to give thetitle compound (25 mg, 59%, TFA salt) as a colorless oil. [M+H]⁺=552.2;[M−H]⁻=550.3; ¹H NMR (400 MHz, CDCl₃): δ 1.28 (t, J=7.15 Hz, 6H), 1.32(d, J=6.05 Hz, 6H), 4.04-4.14 (m, 4H), 4.37-4.48 (m, 4H), 4.59 (dt,J=12.09, 6.05 Hz, 1H), 6.60 (s, 1H), 6.94 (s, 1H), 7.01 (s, 1H), 7.08(s, 1H), 7.43-7.49 (m, 4H), 7.55-7.61 (m, 2H), 9.10 (s, 1 H), ¹⁹F NMR(400 MHz, CDCl₃): 6-75.98, −103.82, −103.86.

Example 123

To a 0° C. solution of Example 122 Part B acid (46.7 mg, 0.139 mmol) inCH₂Cl₂ (1.5 mL) under Ar were successively added dropwise oxalylchloride (250 μL of a 2M solution in 2 M in CH₂Cl₂, 0.5 mmol,) and DMF(15 μL). After 15 min, the reaction was allowed to warm to RT and theyellow reaction was stirred at RT for 3 h. Volatiles were removed invacuo to give Part A compound (68.8 mg, >100% recovery) as an orangeoily solid.

To a 0° C. solution of Example 13 Part E amine (36.7 mg, 0.147 mmol) inTHF (0.4 mL) under Ar were successively added iPr₂NEt (120 μL, 0.689mmol), a solution of Part A compound (24.7 mg, 0.0695 mmol) in CH₂Cl₂(0.4 mL) and finally DMAP (1.7 mg, 0.014 mmol). The reaction was allowedto warm to RT and stirred for 20 h at RT, then was diluted with waterand combined with the crude reaction mixture from a similar experimentusing Part A acid chloride (24.7 mg, 0.0695 mmol) and Example 13 Part Eamine (36.7 mg, 0.147 mmol). The combined reaction mixtures werepartitioned between dilute aqueous NaHCO₃ and CH₂Cl₂. The aqueous layerwas extracted with CH₂Cl₂ (2×), and the combined organic layers weredried (Na₂SO₄) and concentrated in vacuo. The residue was initiallypurified by preparative HPLC(YMC ODS 30×250 mm column, detection at 220nm; flow rate=25 mL/min; continuous gradient from 50% A to 100% B over30 min+7 min hold time at 100% B, where A=90:10:0.1 H₂O:CH3CN:TFA andB=90:10:0.1 CH₃CN:H₂O:TFA). The residue was dissolved in MeOH and passedthrough a MeOH treated cartridge of Polymer Lab StratoSpheres™ SPEPL-HCO₃ MP SPE (500 mg) resin, washing well with MeOH. The filtrate wasconcentrated in vacuo. The residue was dissolved in CH₂Cl₂/MeOH,filtered, and concentrated in vacuo to give the title compound (5.6 mg,7%) as a tan gummy solid. [M+H]⁺=569.3; [M−H]⁻=567.3; ¹H NMR (400 MHz,CDCl₃): δ 1.24 (t, J=7.15 Hz, 6H), 1.30 (d, J=6.05 Hz, 6H), 3.28 (d,J=20.89 Hz, 2H), 3.98-4.09 (m, 4H), 4.36 (t, J=12.37 Hz, 2H), 4.53 (dt,J=12.09, 6.05 Hz, 1H), 6.57 (s, 1H), 6.77 (d, J=3.30 Hz, 1H), 7.02 (s,1H), 7.09 (s, 1H), 7.41-7.49 (m, 3H), 7.51-7.59 (m, 2H), 8.01 (d, J=7.15Hz, 1H); ¹⁹F NMR (400 MHz, CDCl₃): 6-103.73, −103.76, −103.80.

Example 124

To a solution of methyl-3,5-dihydroxy benzoate (10.00 g; 59.5 mmol) inDMF (60.0 mL) under Ar was added K₂CO₃ (12.4 g; 89.7 mmol), followed bythe slow addition of benzyl bromide (10.0 mL; 84.2 mmol) over 10 min.The reaction mixture was stirred at 25° C. for 16 h, then was quenchedwith sat. aqueous NH₄Cl (50 mL) and water (350 mL). The aqueoussuspension was extracted with CH₂Cl₂ (3×50 mL). The combined organicextracts were washed with water and brine, dried (MgSO₄), andconcentrated in vacuo. The crude product was chromatographed (SiO₂;stepwise gradient from 10-20-30-50% solvent B, where solvent A=hexanesand solvent B=EtOAc) to give Part A compound (4.599 g; 30%) as anoff-white powder.

To a 0° C. solution of Part A compound (3.130 g; 12.12 mmol) in THF(52.7 mL) were added (R)-1-methoxypropan-2-ol (1.64 g; 18.18 mmol) andPh₃P (4.77 g; 18.18 mmol), followed by the slow addition of DIAD (3.53mL; 18.18 mmol) via syringe pump. The reaction mixture was stirred at25° C. for 16 h under Ar, then was diluted with water and extracted withEtOAc (3×). The combined organic extracts were washed with 1N aqueousNaOH and brine, dried (MgSO₄) and concentrated in vacuo. The crudeproduct was chromatographed (SiO₂; stepwise gradient from 5-10-30-50%solvent B, where solvent A=hexanes and solvent B=EtOAc) to give Part Bcompound (2.892 g; 53%) as a clear, colorless oil.

A flask containing Part B compound (2.892 g; 8.75 mmol) in MeOH (109 mL)was evacuated and flushed with Ar. 10% Pd/C (0.931 g; 0.875 mmol) wasadded followed by evacuation of the flask and refilling with H₂ (g; 1atmosphere). The reaction was stirred for 2 days under H₂. The reactionmixture was filtered and the catalyst was washed with EtOAc. Thecombined filtrates were concentrated in vacuo to give Part C compound(2.075 g; 83%) as a clear, colorless oil.

To a 0° C. solution of Part C compound (0.125 g; 0.519 mmol) in THF(2.60 mL) were added 2-(4-(ethylthio)phenyl)ethanol (0.208 g; 1.142mmol) and Ph₃P (0.299 g; 1.142 mmol), followed by the slow addition ofDIAD (0.222 mL; 1.142 mmol). The reaction mixture was stirred at 25° C.for 16 h under Ar. The reaction mixture was diluted with water andextracted with EtOAc (3×). The combined organic extracts were washedwith 1N aqueous NaOH and brine, dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (SiO₂; stepwise gradient from5-10-20-30-50% solvent B, where solvent A=hexanes and solvent B=EtOAc)to give Part D compound (0.121 g; 49%) as a clear, yellow oil.

To a solution of Part D compound (0.1208 g; 0.299 mmol) in THF (2.47 mL)and water (0.25 mL) was added LiOH.H₂O (0.014 g; 0.597 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH.H₂O was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄) and concentrated in vacuo to give Part E compound (0.1082 g;76%) as a clear, colorless oil.

To a solution of Part E compound (0.160 g; 0.411 mmol) in DMF (2.05 mL)were added HOAT (0.064 g; 0.47 mmol), Example 13 Part E compound (0.123g; 0.493 mmol), and DIPEA (0.08 mL; 0.47 mmol), and lastly, EDCI (0.091g; 0.47 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O: CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (80.4 mg; 31%) as a clear,colorless oil. [M+H]⁺=623.2.

Example 125

To a 0° C. solution of Example 124 Part C compound (0.125 g; 0.519 mmol)in THF (2.60 mL) was added 2-(4-(methylthio)phenyl)ethanol (0.208 g;1.142 mmol) and Ph₃P (0.299 g; 1.142 mmol), followed by the slowaddition of DIAD (0.222 mL; 1.142 mmol). The reaction mixture wasstirred at 25° C. for 16 h under Ar, then was diluted with water andextracted with EtOAc (3×). The combined organic extracts were washedwith 1N aqueous NaOH and brine, dried (MgSO₄) and concentrated in vacuo.The crude product was chromatographed (SiO₂; step gradient from5-10-20-30-50% solvent B, where solvent A=hexanes and solvent B=EtOAc)to give Part A compound (0.121 g; 49%) as a clear, yellow oil.

To a solution of Part A compound (0.1208 g; 0.299 mmol) in THF (2.47 mL)and water (0.25 mL) was added LiOH.H₂O (0.014 g; 0.597 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄) and concentrated in vacuo to give Part B compound (0.1082 g;76%) as a clear, colorless oil.

To a solution of Example 13 Part E compound (0.13 g; 0.51 mmol) in DMF(2.13 mL) were added HOAT (0.067 g; 0.49 mmol), Part B compound (0.16 g;0.43 mmol), DIPEA (0.63 mL; 0.49 mmol), and, lastly, EDCI (0.094 g; 0.49mmol). The reaction mixture was stirred at 25° C. for 16 h. Water wasadded, and the mixture was extracted with EtOAc (3×). The combinedorganic extracts were washed with sat. aqueous NH₄Cl, sat. aqueousNaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. The residuewas purified by preparative HPLC(YMC reverse phase ODS-5u 30×100 mmcolumn; flow rate=40 mL/min, 25 to 100% solvent B over 12 min, wheresolvent A=90:10:0.1 H₂O: CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (47.0 mg; 17%) as a clear,colorless oil. [M+H]⁺=609.1.

Example 126

To Example 124 Part F compound (0.04 g; 0.07 mmol) in iPrOH (1.46 mL)and water (0.73 mL) was added oxone (0.09 g; 0.15 mmol). The reactionmixture was stirred for 16 h at 25° C., then was filtered and extractedwith EtOAc. The filtrate was partitioned between water and brine. Theorganic layer was dried (MgSO₄) and concentrated in vacuo. The residuewas purified by preparative HPLC(YMC reverse phase ODS-5 u 30×100 mmcolumn; flow rate=40 mL/min, 25 to 100% solvent B over 12 min, wheresolvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1 CH₃CN:H₂O:TFA)to give the title compound (48.0 mg; 55%) as a white solid.[M+H]⁺=655.3; ¹H NMR (400 MHz, CDCl₃): δ 1.16-1.29 (m, 12H), 2.98-3.08(m, J=7.33, 7.33, 7.33 Hz, 2H), 3.08-3.18 (m, J=6.32, 6.32 Hz, 2H), 3.22(s, 1 H), 3.28 (s, 1H), 3.33 (s, 3H), 3.41-3.54 (m, 2H), 4.01-4.13 (m,4H), 4.24 (t, J=6.32 Hz, 2H), 4.61-4.70 (m, J=10.17, 6.32 Hz, 1H),6.64-6.70 (m, 1H), 6.93-6.97 (m, J=3.30 Hz, 1H), 7.29 (d, J=17.59 Hz,2H), 7.42 (d, J=8.24 Hz, 2H), 7.78 (d, J=8.25 Hz, 2H).

Example 127

To Example 125 Part C compound (0.04 g; 0.07 mmol) in iPrOH (1.46 mL)and water (0.73 mL) was added oxone (0.09 g; 0.15 mmol). The reactionmixture was stirred for 16 h at 25° C., then was filtered and rinsedwith EtOAc. The filtrate was washed with water and brine, dried (MgSO₄)and concentrated in vacuo. The residue was purified by preparativeHPLC(YMC reverse phase ODS-5 u 30×100 mm column; flow rate=40 mL/min, 25to 100% solvent B over 12 min, where solvent A=90:10:0.1 H₂O: CH₃CN:TFAand solvent B=90:10:0.1 CH₃CN:H₂O:TFA) to give the title compound (14.2mg; 33%) as a white solid. [M+H]⁺=641.3; ¹H NMR (400 MHz, CDCl₃): δ1.21-1.30 (m, J=7.42, 7.42 Hz, 9H), 2.97 (s, 3H), 3.12 (t, J=6.05 Hz,2H), 3.26 (s, 1H), 3.29-3.36 (m, 4H), 3.41-3.55 (m, 2H), 4.03-4.16 (m, 4H), 4.25 (t, J=6.32 Hz, 2H), 4.60-4.72 (m, 1H), 6.62-6.71 (m, 1H),6.91-7.01 (m, J=3.85 Hz, 1H), 7.32 (d, J=16.49 Hz, 2H), 7.43 (d, J=8.25Hz, 2H), 7.81 (d, J=8.24 Hz, 2H).

Example 128

To Example 124 Part C compound (0.100 g; 0.416 mmol) was added2-(2-fluorophenyl)ethanol (0.24 g; 1.67 mmol in toluene; 2.08 mL),followed by a suspension of Example 97 Part B compound (0.68 g; 1.67mmol) in CH₂Cl₂ (7.6 mL). The reaction mixture was stirred for 16 h at25° C., then was diluted with water and extracted with EtOAc (3×). Thecombined organic extracts were washed with 1N aqueous NaOH and brine,dried (MgSO₄) and concentrated in vacuo. The crude product waschromatographed (SiO₂; step gradient from 10-20-30% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.146 g;90%).

To a solution of Part A compound (0.100 g; 0.27 mmol) in THF (2.23 mL)and water (0.22 mL) was added LiOH.H₂O (0.013 g; 0.54 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH.H₂O was added. The reaction mixture wasstirred at 45° C. for 16 h, then cooled to RT. Volatiles were removed invacuo and the remaining aqueous solution was acidified with 0.5N aqueousHCl to pH<2. The aqueous layer was re-extracted with EtOAc (3×). Thecombined organic extracts were washed with brine, dried (MgSO₄) andconcentrated in vacuo to give Part B compound (0.107 g; 100%).

To a solution of Example 13 Part E compound (0.073 g; 0.29 mmol) in DMF(1.21 mL) were added HOAT (0.038 g; 0.278 mmol), Part B compound (0.084g; 0.242 mmol), and DIPEA (0.049 mL; 0.278 mmol) and, lastly, EDCI(0.053 g; 0.278 mmol). The reaction mixture was stirred at 25° C. for 16h. Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 μm30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (69.7 mg; 49%) as a clear,colorless oil. [M+H]⁺=581.5; ¹H NMR (400 MHz, CDCl₃) δ 1.21-1.26 (m,9H), 3.06 (t, J=6.87 Hz, 2H), 3.21 (s, 1H), 3.26 (s, 1H), 3.31-3.35 (m,3H), 3.41-3.53 (m, 2H), 3.98-4.10 (m, 4H), 4.18 (t, J=6.60 Hz, 2H),4.61-4.71 (m, 1H), 6.63-6.70 (m, 1H), 6.84-7.06 (m, 3H), 7.10-7.17 (m,1H), 7.18-7.25 (m, J=12.64 Hz, 3H), 7.26-7.30 (m, 1H).

Example 129

To Example 124 Part C compound (0.100 g; 0.416 mmol) were added2-(3-fluorophenyl)ethanol (0.24 g; 1.67 mmol in toluene (2.08 mL)followed by a suspension of Example 97 Part B compound (0.68 g; 1.67mmol) in CH₂Cl₂ (7.6 mL). The reaction mixture was stirred for 16 h at25° C., then was diluted with water and extracted with EtOAc (3×). Thecombined organic extracts were washed with 1N aqueous NaOH and brine,dried (MgSO₄), and concentrated in vacuo. The crude product waschromatographed (SiO₂; step gradient from 10-20-30% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.146 g;90%).

To a solution of Part A compound (0.100 g; 0.27 mmol) in THF (2.23 mL)and water (0.22 mL) was added LiOH.H₂O (0.013 g; 0.54 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH.H₂O was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give Part B compound (0.107 g;100%).

To a solution of Example 13 Part E compound (0.092 g; 0.37 mmol) in DMF(1.54 mL) were added HOAT (0.038 g; 0.35 mmol) Part B compound (0.107 g;0.308 mmol), DIPEA (0.062 mL; 0.35 mmol) and, lastly, EDCI (0.068 g;0.35 mmol). The reaction mixture was stirred at 25° C. for 16 h. Waterwas added, and the mixture was extracted with EtOAc (3×). The combinedorganic extracts were washed with sat. aqueous NH₄Cl, sat. aqueousNaHCO₃, and brine, dried (MgSO₄) and concentrated in vacuo. The residuewas purified by preparative HPLC(YMC reverse phase ODS-5 μm 30×100 mmcolumn; flow rate=40 mL/min, 25 to 100% solvent B over 12 min, wheresolvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1 CH₃CN:H₂O:TFA)to give the title compound (78.5 mg; 44%) as a clear, colorless oil.[M+H]⁺=581.1; ¹H NMR (400 MHz, CDCl₃) δ 1.17-1.28 (m, 9H), 3.01 (t,J=6.32 Hz, 2H), 3.24 (s, 1H), 3.26-3.36 (m, 4H), 3.42-3.54 (m, 2H),4.00-4.14 (m, 4H), 4.19 (t, J=6.32 Hz, 2H), 4.62-4.73 (m, 1H), 6.64-6.70(m, 1H), 6.79-6.88 (m, J=8.52, 8.52 Hz, 1H), 6.88-7.02 (m, 3H),7.12-7.22 (m, 1H), 7.25-7.30 (m, 1H), 7.28 (s, 1H), 7.33 (s, 1H),7.31-7.36 (m, 1H).

Example 130

To Example 124 Part C compound (0.100 g; 0.416 mmol) was added4-(2-hydroxyethyl)benzonitrile (0.09 g; 0.62 mmol in toluene (2.08 mL)followed by a suspension of Example 97 Part B compound (0.26 g; 0.62mmol) in CH₂Cl₂ (7.14 mL). The reaction mixture was stirred for 16 h at25° C., then was diluted with water and extracted with EtOAc (3×). Thecombined organic extracts were washed with 1N aqueous NaOH and brine,dried (MgSO₄) and concentrated in vacuo. The crude product waschromatographed (SiO₂; stepwise gradient from 5-10-20% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.100 g;63%).

To a solution of Part A compound (0.15 g; 0.40 mmol) in THF (3.27 mL)and water (0.33 mL) was added LiOH.H₂O (0.019 g; 0.79 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give Part B compound (0.140 g;85%).

To a solution of Example 13 Part E compound (0.114 g; 0.454 mmol) in DMF(1.89 mL) were added HOAT (0.059 g; 0.44 mmol), Part B compound (0.134g; 0.378 mmol), DIPEA (0.076 mL; 0.35 mmol), and, lastly, EDCI (0.083 g;0.435 mmol). The reaction mixture was stirred at 25° C. for 16 h. Waterwas added, and the mixture was extracted with EtOAc (3×). The combinedorganic extracts were washed with sat. aqueous NH₄Cl, sat. aqueousNaHCO₃, and brine, dried (MgSO₄) and concentrated in vacuo. The residuewas purified by preparative HPLC(YMC reverse phase ODS-5 u 30×100 mmcolumn; flow rate=40 mL/min, 25 to 100% solvent B over 12 min, wheresolvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1 CH₃CN:H₂O:TFA)to give the title compound (86.5 mg; 39%) as a tacky, clear, whitesolid. [M+H]⁺=588.1; ¹H NMR (400 MHz, CDCl₃): δ 1.18-1.27 (m, 9H), 3.07(t, J=6.32 Hz, 2H), 3.20 (s, 1H), 3.25 (s, 1H), 3.33 (s, 3H), 3.40-3.53(m, 2H), 3.97-4.09 (m, 4H), 4.19 (t, J=6.32 Hz, 2H), 4.55-4.66 (m,J=3.85 Hz, 1 H), 6.63 (s, 1H), 6.84-6.90 (m, J=3.30 Hz, 1H), 7.17-7.21(m, J=3.85 Hz, 1H), 7.24 (s, 1H), 7.33 (d, J=8.25 Hz, 2H), 7.53 (d,J=8.25 Hz, 2H).

Example 131

To Example 124 Part C compound (0.100 g; 0.416 mmol) were added asolution of 2-(4-fluororophenyl)ethanol (0.58 g; 4.16 mmol) in toluene(2.18 mL) and a suspension of Example 97 Part B compound (1.71 g; 4.16mmol) in CH₂Cl₂ (7.60 mL). The reaction mixture was stirred for 16 h at25° C., then was diluted with water and extracted with EtOAc (3×). Thecombined organic extracts were washed with 1N aqueous NaOH and brine,dried (MgSO₄) and concentrated in vacuo. The crude product waschromatographed (SiO₂; step gradient from 5-10-15-20% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.137 g;86%).

To a solution of Part A compound (0.14 g; 0.38 mmol) in THF (3.27 mL)and water (0.33 mL) was added LiOH.H₂O (0.010 g; 0.38 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH less than 2. The aqueous layer was re-extractedwith EtOAc (3×). The combined organic extracts were washed with brine,dried (MgSO₄), and concentrated in vacuo to give Part B compound (0.122g; 78%).

To a solution of Example 13 Part E compound (0.106 g; 0.422 mmol) in DMF(1.76 mL) were added HOAT (0.055 g; 0.404 mmol), Part B compound (0.122g; 0.351 mmol), DIPEA (0.071 mL; 0.404 mmol), and, lastly, EDCI (0.077g; 0.404 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (80.0 mg; 39%) as a clear,pale yellow oil. [M+H]⁺=581.2; ¹H NMR (400 MHz, CDCl₃): δ 1.21-1.33 (m,9 H), 3.06 (t, 2H), 3.25 (s, 1H), 3.31 (s, 1H), 3.39 (s, 3H), 3.45-3.60(m, 2H), 4.00-4.15 (m, 4H), 4.19 (t, 2H), 4.60-4.70 (m, 1H), 6.65-6.72(m, 1H), 6.88-6.94 (m, 1H), 6.99 (t, 2H), 7.13-7.27 (m, 4H), 11.77 (s,1H).

Example 132

To a cold solution (0° C.) of Example 124 Part C compound (0.100 g;0.416 mmol) in THF (2.08 mL) were added (S)-(+)-3-Hydroxytetrahydrofuran(0.074 mL; 0.916 mmol) and Ph₃P (0.24 g; 0.916 mmol), followed by theslow addition of DIAD (0.178 mL; 0.916 mmol). The reaction mixture wasstirred at 25° C. for 16 h under at atmosphere of Ar. The reactionmixture was diluted with water and extracted with EtOAc (3×). Thecombined organic extracts were washed with 1N aqueous NaOH and brine,dried (MgSO₄), and concentrated in vacuo. The crude product waschromatographed (SiO₂; stepwise gradient from 10-15-20% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.105 g;75%).

To a solution of Part A compound (0.105 g; 0.337 mmol) in THF (2.79 mL)and water (0.279 mL) was added LiOH.H₂O (0.028 g; 0.674 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give Part B compound (0.0964 g;97%).

To a solution of Example 13 Part E compound (0.098 g; 0.390 mmol) in DMF(1.63 mL) were added HOAT (0.051 g; 0.374 mmol), Part B compound (0.096g; 0.325 mmol), DIPEA (0.065 mL; 0.374 mmol), and, lastly, EDCI (0.072g; 0.374 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat.aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (84.3 mg; 49%) as a clear,colorless oil. [M+H]⁺=529.1; ¹H NMR (400 MHz, CDCl₃): δ 1.19-1.34 (m,9H), 2.06-2.30 (m, 2H), 3.25 (s, 1H), 3.30 (s, 1H), 3.39 (s, 3H),3.43-3.61 (m, 2H), 3.84-4.00 (m, 4H), 4.00-4.13 (m, 4H), 4.54-4.64 (m,1H), 4.91-5.00 (m, 1H), 6.62-6.70 (m, 1H), 6.80-6.88 (m, J=3.85 Hz, 1H),7.06 (s, 1H), 7.13 (s, 1H), 10.53 (s, 1H).

Example 133

To a 0° C. solution of Example 124 Part C compound (0.100 g; 0.416 mmol)in THF (2.08 mL) were added (R)-(−)-3-hydroxytetrahydrofuran (0.033 mL;0.416 mmol) and Ph₃P (0.24 g; 0.916 mmol), followed by the slow additionof DIAD (0.178 mL; 0.916 mmol). The reaction mixture was stirred at 25°C. for 16 h under Ar, then was diluted with water and extracted withEtOAc (3×). The combined organic extracts were washed with 1N aqueousNaOH and brine, dried (MgSO₄), and concentrated in vacuo. The crudeproduct was chromatographed (SiO₂; stepwise gradient from 10-15-20%solvent B, where solvent A=hexanes and solvent B=EtOAc) to give Part Acompound (0.088 g; 62%).

To a solution of Part A compound (0.088 g; 0.282 mmol) in THF (2.33 mL)and water (0.233 mL) was added LiOH.H₂O (0.024 g; 0.565 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄) and concentrated in vacuo to give Part B compound (0.0654 g;74%).

To a solution of Example 13 Part E compound (0.066 g; 0.265 mmol) in DMF(1.10 mL) were added HOAT (0.035 g; 0.254 mmol), Part B compound (0.065g; 0.221 mmol), DIPEA (0.044 mL; 0.254 mmol), and, lastly, EDCI (0.049g; 0.254 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (50.5 mg; 43%) as a clear,colorless oil. [M+H]⁺=529.1; ¹H NMR (400 MHz, CDCl₃): δ 1.21-1.33 (m,9H), 2.03-2.17 (m, 1H), 2.17-2.28 (m, 1H), 3.25 (s, 1H), 3.31 (s, 1H),3.38 (s, 3H), 3.44-3.53 (m, 1H), 3.52-3.59 (m, 1H), 3.68 (s, 2H),3.83-3.92 (m, 1H), 3.93-4.01 (m, 2H), 4.03-4.12 (m, 3H), 4.57-4.67 (m,1H), 4.96-5.02 (m, J=2.20 Hz, 1 H), 6.67 (s, 1H), 6.85-6.92 (m, J=3.85Hz, 1H), 7.13 (s, 1H), 7.20 (s, 1H).

Example 134

To a 0° C. solution of Example 124 Part C compound (0.125 g; 0.519 mmol)in THF (2.60 mL) were added 2-(methylthio)ethanol (0.105 mL; 1.14 mmol)and Ph₃P (0.30 g; 1.142 mmol), followed by the slow addition of DIAD(0.222 mL; 1.142 mmol). The reaction mixture was stirred at 25° C. for16 h under Ar, then was diluted with water and extracted with EtOAc(3×). The combined organic extracts were washed with 1N aqueous NaOH andbrine, dried (MgSO₄), and concentrated in vacuo. The crude product waschromatographed (SiO₂; step gradient from 20-30-50-60% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (61.8 mg;38%).

To a solution of Part A compound (0.062 g; 0.197 mmol) in THF (1.63 mL)and water (0.163 mL) was added LiOH.H₂O (0.016 g; 0.393 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give Part B compound (0.052 g;88%).

To a solution of Example 13 Part E compound (0.059 g; 0.236 mmol) in DMF(0.98 mL) were added HOAT (0.031 g; 0.226 mmol), Part B compound (0.059g; 0.196 mmol), DIPEA (0.034 mL; 0.196 mmol), and, lastly, EDCI (0.043g; 0.226 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (62.3 mg; 60%) as a clear,colorless oil. [M+H]⁺=533.4; ¹H NMR (400 MHz, CDCl₃): δ 1.23-1.31 (m,9H), 2.15 (s, 3H), 3.27 (s, 1H), 3.31-3.37 (m, 4H), 3.44-3.56 (m, 2H),3.99-4.15 (m, 4H), 4.19 (t, 2H), 4.65-4.77 (m, 1H), 6.69-6.74 (m, 1H),6.95-7.00 (m, 1H), 7.28-7.33 (m, 1H), 7.35-7.40 (m, 1H).

Example 135

To a 0° C. solution of Example 134 Part C compound (0.040 g; 0.075 mmol)in CH₂Cl₂ (0.75 mL) was added mCPBA (0.026 g; 0.15 mmol). The reactionmixture was stirred for 1 h at 0° C., then was warmed to RT. Thereaction mixture was filtered, quenched with sat. aqueous NaHCO₃, andextracted with CH₂Cl₂ (3×). The combined organic extracts were washedwith brine, dried (MgSO₄), and concentrated in vacuo. The residue waspurified by preparative HPLC(YMC reverse phase ODS-5u 30×100 mm column;flow rate=40 mL/min, 25 to 100% solvent B over 12 min, where solventA=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1 CH₃CN:H₂O:TFA) to givethe title compound (10.6 mg; 25%) as a clear, colorless oil.[M+H]⁺=565.2; ¹H NMR (400 MHz, CDCl₃): δ 1.26-1.34 (m, 9H), 3.05 (s, 3H), 3.29 (s, 1H), 3.34 (s, 1H), 3.39 (s, 4H), 3.43 (t, 3H), 3.49-3.60(m, 2H), 4.07-4.18 (m, 4H), 4.52 (t, J=10.44 Hz, 3H), 4.69-4.79 (m, 1H),6.72-6.78 (m, 1H), 6.99-7.05 (m, 1H), 7.40 (s, 1H), 7.45 (s, 1H).

Example 136

To a cold solution (0° C.) of 2-hydroxy-methylbenzoate (0.20 g; 1.31mmol) in THF (5.70 mL) were added (R)-(−)-1-methoxy-2-propanol (0.178 g;1.97 mmol) and Ph₃P (0.517 g; 1.97 mmol), followed by the slow additionof DIAD (0.398 g; 1.97 mmol). The reaction mixture was stirred at 25° C.for 16 h under Ar, then was diluted with water and extracted with EtOAc(3×). The combined organic extracts were washed with 1N aqueous NaOH andbrine, dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 10-20-30% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.219 g;74%).

To a solution of Part A compound (0.219 g; 0.975 mmol) in THF (3.75 mL)and water (1.19 mL) was added LiOH.H₂O (0.049 g; 1.07 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 50° C. for 2 h, then cooled to RT. Volatiles were removed invacuo, and the remaining aqueous solution was acidified with 0.5Naqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc (3×).The combined organic extracts were washed with brine, dried (MgSO₄), andconcentrated in vacuo to give Part B compound (0.221 g; 100%).

To a solution of Example 13 Part E compound (0.043 g; 0.171 mmol) in DMF(0.55 mL) were added HOAT (0.022 g; 0.164 mmol), Part B compound (0.030g; 0.143 mmol), DIPEA (0.029 mL; 0.164 mmol), and, lastly, EDCI (0.031g; 0.164 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 μm,30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (17.3 mg; 27%) as a tacky,pale yellow oil. [M+H]⁺=443.3; ¹H NMR (400 MHz, CDCl₃): δ 1.22-1.30 (m,9 H), 3.30 (s, 1H), 3.35 (s, 3H), 3.35 (s, 4H), 3.47-3.58 (m, 2H),4.01-4.16 (m, 4 H), 4.75-4.83 (m, 1H), 6.96-7.00 (m, J=3.85 Hz, 1H),7.14-7.18 (m, J=8.24, 2.20 Hz, 1H), 7.37 (t, J=7.97 Hz, 1H), 7.70 (d,J=7.70 Hz, 2H), 7.70 (d, J=7.70 Hz, 1H).

Example 137

To a solution of Example 33 Part A acid (0.058 g; 0.17 mmol) in Et₂O(1.30 mL) under Ar was added TMSI (0.203 g; 1.01 mmol). The reactionmixture was stirred at 25° C. for 16 h, then was cooled to −40° C.,cautiously quenched with water, and concentrated in vacuo. The residuewas diluted with EtOAc and 1N aqueous HCl. The organic layer was washedwith 10% (w/v) aqueous Na₂S₂O₃, washed with brine, dried (MgSO₄), andconcentrated in vacuo to give Part A compound (0.056 g; 99%) as a yellowoil.

A solution of TBSCl (0.076 g; 0.504 mmol) in DMF (0.37 mL) was added toPart A compound (0.056 g; 0.17 mmol). Imidazole (0.069 g; 1.01 mmol) wasadded, and the reaction mixture was stirred for 2 h at 25° C., then waspartitioned between EtOAc and sat. aqueous NH₄Cl. The organic phase waswashed with sat. aqueous NH₄Cl and brine, dried (MgSO₄), andconcentrated in vacuo. The residue was chromatographed (SiO₂; stepwisegradient from 20-25-30% solvent B, where solvent A=hexanes and solventB=EtOAc) to give Part B compound (0.057 g; 76%).

To a solution of Example 13 Part E compound (0.038 g; 0.152 mmol) in DMF(0.49 mL) were added HOAT (0.020 g; 0.146 mmol), Part B compound (0.057g; 0.127 mmol), DIPEA (0.026 mL; 0.146 mmol), and, lastly, EDCI (0.028g; 0.146 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine. The organic layer was dried (MgSO₄), andconcentrated in vacuo to give Part C compound (0.063 g; 74%) as a clear,gold oil.

To a 0° C. solution of Part C compound (0.063; 0.094 mmol) in THF (0.47mL) was added TBAF (0.090 mL of a 1 M solution; 0.094 mmol). Thereaction was stirred for 1 h at 0° C. and an addition equivalent of TBAF(0.090 mL of a 1 M solution; 0.094 mmol) was added. The reaction wasstirred at 0° C. for another 1 h, then was concentrated in vacuo. Theresidue was partitioned between EtOAc and brine. The organic layer waswashed with brine, dried (MgSO₄), and concentrated in vacuo. The residuewas purified by preparative HPLC(YMC reverse phase ODS-5 μm 30×100 mmcolumn; flow rate=40 mL/min, 25 to 100% solvent B over 12 min, wheresolvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1 CH₃CN:H₂O:TFA)to give the title compound (23.6 mg; 45%) as a clear, colorless oil.[M+H]⁺=563.5; ¹H NMR (400 MHz, CDCl₃): δ 1.16-1.31 (m, J=11.82, 6.32 Hz,12H), 1.98 (s, 1H), 2.77-2.87 (m, J=13.74 Hz, 1H), 2.93-3.02 (m, J=13.74Hz, 1H), 3.27 (s, 1H), 3.32 (s, 1H), 3.61-3.69 (m, 1H), 3.69-3.76 (m,1H), 4.01-4.14 (m, 4H), 4.60-4.72 (m, 2H), 6.62-6.66 (m, J=2.20, 2.20Hz, 1H), 6.96 (d, J=3.85 Hz, 1H), 7.09-7.24 (m, 5H), 7.28 (s, 1H) 7.32(s, 1H).

Example 138

A solution of Example 124 Part C compound (0.100 g; 0.416 mmol),phenylboronic acid (0.102 g; 0.832 mmol), copper (II) acetate (0.151 g;0.832 mmol), Et₃N (0.211 g; 2.08 mmol), and freshly activated 4 Åmolecular sieves (1.2 g) in CH₂Cl₂ (8.32 mL) was stirred at 25° C. for16 h. Additional solvent (8 mL), two equivalents each of boronic acid,copper (II) acetate, and Et₃N were added after 2 days. After a total of5 days, 70% conversion was observed. The reaction mixture was filteredand washed with CH₂Cl₂. The combined filtrates were concentrated invacuo, and the residue was partitioned between EtOAc and 1N aqueous HCl.The organic layer was washed with sat. aqueous NaHCO₃ and brine, dried(MgSO₄), and concentrated in vacuo. The crude product waschromatographed (SiO₂; step gradient from 10-20-30% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (70.2 mg;83% yield based on recovered starting material).

To a solution of Part A compound (0.070 g; 0.222 mmol) in THF (0.85 mL)and water (0.27 mL) was added LiOH.H₂O (0.010 g; 0.244 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH.H₂O was added. The reaction mixture wasstirred at 45° C. for an additional 3 h, then was cooled to RT.Volatiles were removed in vacuo, and the remaining aqueous solution wasacidified with 0.5N aqueous HCl to pH<2. The aqueous layer wasre-extracted with EtOAc (3×). The combined organic extracts were washedwith brine, dried (MgSO₄), and concentrated in vacuo to give Part Bcompound (0.060 g; 90%).

To a solution of Example 13 Part E compound (0.030 g; 0.119 mmol) in DMF(0.38 mL) were added HOAT (0.016 g; 0.114 mmol), Part B compound (0.03g; 0.099 mmol), DIPEA (0.020 mL; 0.114 mmol), and, lastly, EDCI (0.022g; 0.114 mmol). The reaction mixture was stirred at 25° C. for 16 h. Anadditional equivalent of Example 13 Part E compound was added, and thereaction mixture stirred at 25° C. for a further 16 h with no furtherconversion. Water was added, and the mixture was extracted with EtOAc(3×). The combined organic extracts were washed with sat. aqueous NH₄Cl,sat. aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated invacuo. The residue was purified by preparative HPLC(YMC reverse phaseODS-5 μm 30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent Bover 12 min, where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solventB=90:10:0.1 CH₃CN:H₂O:TFA) to give the title compound (0.010 mg; 20%) asa tacky, yellow glass. [M+H]⁺=535.5; ¹H NMR (400 MHz, CDCl₃): δ1.21-1.31 (m, 9H), 3.26 (s, 1H), 3.29-3.36 (m, 4H), 3.46-3.53 (m, 2H),4.02-4.15 (m, 4H), 4.73-4.87 (m, 1H), 6.74-6.81 (m, 1H), 6.92-7.02 (m,3H), 7.09 (t, J=7.42 Hz, 1H), 7.25-7.34 (m, 3H), 7.48 (s, 1H).

Example 139

To a 0° C. solution of Example 124 Part C compound (0.110 g; 0.458 mmol)in THF (2.29 mL) were added 3-(methylthio)propan-1-ol (0.107 mL; 1.01mmol) and Ph₃P (0.265 g; 1.01 mmol), followed by the slow addition ofDIAD (0.195 mL; 1.01 mmol). The reaction mixture was stirred at 25° C.for 16 h under Ar, then was diluted with water and extracted with EtOAc(3×). The combined organic extracts were washed with 1N aqueous NaOH andbrine, dried (MgSO₄), and concentrated in vacuo. The crude product waschromatographed (SiO₂; stepwise gradient from 10-20% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.110 g;73%).

To a 0° C. solution of Part A compound (0.110 g; 0.334 mmol) in CH₂Cl₂(3.34 mL) was added mCPBA (0.115 g; 0.67 mmol). The reaction mixture wasstirred for 1 h at 0° C., then sat. aqueous NaHCO₃ was added and themixture was extracted with CH₂Cl₂ (3×). The combined organic extractswere washed with brine, dried (MgSO₄), and concentrated in vacuo to givePart B compound (0.161 g; 88%).

To a solution of Part C compound (0.162 g; 0.450 mmol) in THF (1.73 mL)and water (0.549 mL) was added LiOH.H₂O (0.021 g; 0.495 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then cooled to RT. Volatiles were removed invacuo, and the remaining aqueous solution was acidified with 0.5Naqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc (3×).The combined organic extracts were washed with brine, dried (MgSO₄), andconcentrated in vacuo to give Part C compound (0.147 g; 94%).

To a solution of Example 13 Part E compound (0.026 g; 0.104 mmol) in DMF(0.33 mL) were added HOAT (0.014 g; 0.100 mmol), Part C compound (0.030g; 0.087 mmol), DIPEA (0.017 mL; 0.100 mmol), and, lastly, EDCI (0.019g; 0.100 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (8 mg, 16% yield) as a whitesolid lyophilate. [M+H]⁺=579.4; ¹H NMR (400 MHz, CDCl₃): δ 1.14-1.28 (m,9 H), 2.20-2.33 (m, 2H), 2.89 (s, 3H), 3.13-3.26 (m, 4H), 3.33 (s, 3H),3.40-3.54 (m, 2H), 3.92-4.05 (m, 4H), 4.05-4.12 (m, J=5.77, 5.77 Hz,2H), 4.53-4.63 (m, 1 H), 6.61-6.65 (m, 1H), 6.78-6.86 (m, J=3.85 Hz,1H), 7.14 (s, 1H), 7.19 (s, 1H).

Example 140

To a 0° C. solution of Example 124 Part C compound (0.110 g; 0.458 mmol)in THF (2.29 mL) were added (S)-(+)-1-phenyl-2-propanol (0.138 mL; 1.01mmol) and Ph₃P (0.265 g; 1.01 mmol), followed by the slow addition ofDIAD (0.195 mL; 1.01 mmol). The reaction mixture was stirred at 25° C.for 16 h under Ar, then was diluted with water and extracted with EtOAc(3×). The combined organic extracts were washed with 1N aqueous NaOH andbrine, dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 5-10% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.133 g;81%).

To a solution of Part A compound (0.133 g; 0.371 mmol) in THF (1.43 mL)and water (0.45 mL) was added LiOH.H₂O (0.017 g; 0.408 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then cooled to RT. Volatiles were removed invacuo, and the remaining aqueous solution was acidified with 0.5Naqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc (3×).The combined organic extracts were washed with brine, dried (MgSO₄), andconcentrated in vacuo to give Part B compound (0.123 g; 96%).

To a solution of Example 13 Part E compound (0.026 g; 0.105 mmol) in DMF(0.34 mL) were added HOAT (0.014 g; 0.100 mmol), Part B compound (0.030g; 0.087 mmol), DIPEA (0.017 mL; 0.100 mmol), and, lastly, EDCI (0.019g; 0.100 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (16.4 mg; 33%) as a clear,colorless oil. [M+H]⁺=577.4; ¹H NMR (400 MHz, CDCl₃): δ 1.04-1.32 (m, 12H), 2.65-2.86 (m, J=13.74 Hz, 1H), 2.88-3.06 (m, 1H), 3.10-3.25 (m,J=20.89 Hz, 2H), 3.32 (s, 3H), 3.36-3.55 (m, 2H), 3.85-4.05 (m, J=7.15Hz, 4H), 4.34-4.63 (m, 2H), 6.41-6.66 (m, 1H), 6.67-6.81 (m, 1H),6.95-7.07 (m, 2H), 7.08-7.29 (m, 5H), 10.44 (s, 1H), 10.44 (s, 1H).

Example 141

To a solution of 3-hydroxy-methylbenzoate (0.500 g; 3.29 mmol) in DMF(8.23 mL) were added K₂CO₃ (0.908 g; 6.57 mmol) andfluoro-4-(methylsulfonyl)benzene (0.573 g; 3.29 mmol). The reactionmixture was stirred at 120° C. for 2 days under Ar, then cooled to RT.Volatiles were removed in vacuo. The residue was partitioned betweensat. aqueous NaHCO₃ and EtOAc. The organic layer was washed with 1Naqueous HCl and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was chromatographed (SiO₂; stepwise gradient from 20-30-40%solvent B, where solvent A=hexanes and solvent B=EtOAc) to give Part Acompound (0.583 g; 58%).

To a solution of Part A compound (0.200 g; 0.653 mmol) in THF (2.51 mL)and water (0.80 mL) was added LiOH.H₂O (0.030 g; 0.718 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 50° C. for 2 h, then cooled to RT. Volatiles were removed invacuo, and the remaining aqueous solution was acidified with 0.5Naqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc (3×).The combined organic extracts were washed with brine, dried (MgSO₄), andconcentrated in vacuo to give Part B compound (0.176 g; 92%).

To a solution of Example 13 Part E compound (0.309 g; 0.124 mmol) in DMF(0.40 mL) were added HOAT (0.016 g; 0.118 mmol), Part B compound (0.030g; 0.103 mmol), DIPEA (0.021 mL; 0.118 mmol), and, lastly, EDCI (0.023g; 0.118 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (14.7 mg; 27%) as a tacky,white solid. [M+H]⁺=525.3; ¹H NMR (400 MHz, CDCl₃): δ 1.20 (t, J=7.15Hz, 6 H), 2.99 (s, 3H), 3.21 (s, 1H), 3.26 (s, 1H), 3.95-4.08 (m, 4H),6.85-6.92 (m, J=3.30 Hz, 1H), 7.00-7.10 (m, J=8.79 Hz, 2H), 7.24-7.32(m, J=7.70 Hz, 1H), 7.53 (t, J=7.97 Hz, 1H), 7.77 (s, 1H), 7.74-7.80 (m,1H), 7.84 (d, J=8.79 Hz, 2H), 7.92 (d, J=7.70 Hz, 1H).

Example 142

To a 0° C. solution of Example 124 Part C compound (0.110 g; 0.458 mmol)in THF (2.29 mL) were added benzyl alcohol (0.109 mL; 1.01 mmol) andPh₃P (0.265 g; 1.01 mmol), followed by the slow addition of DIAD (0.195mL; 1.01 mmol). The reaction mixture was stirred at 25° C. for 16 hunder Ar, then was diluted with water and extracted with EtOAc (3×). Thecombined organic extracts were washed with 1N aqueous NaOH and brine,dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; step gradient from 10-15-20% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.160 g;100%).

To a solution of Part A compound (0.160 g; 0.483 mmol) in THF (1.86 mL)and water (0.59 mL) was added LiOH.H₂O (0.022 g; 0.532 mmol). Thereaction mixture was stirred at 45° C. for 2 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then cooled to RT. Volatiles were removed invacuo, and the remaining aqueous solution was acidified with 0.5Naqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc (3×).The combined organic extracts were washed with brine, dried (MgSO₄), andconcentrated in vacuo to give Part B compound (0.137 g; 90%).

To a solution of Example 13 Part E compound (0.029 g; 0.114 mmol) in DMF(0.37 mL) were added HOAT (0.015 g; 0.109 mmol), Part B compound (0.030g; 0.095 mmol), DIPEA (0.019 mL; 0.109 mmol), and, lastly, EDCI (0.021g; 0.109 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (18.6 mg; 36%) as a clear,colorless oil. [M+H]⁺=549.2; ¹H NMR (400 MHz, CDCl₃): δ 1.13-1.29 (m,9H), 3.19 (s, 1H), 3.24 (s, 2H), 3.33 (s, 3H), 3.39-3.46 (m, 1H),3.46-3.53 (m, 1H), 3.89-4.04 (m, 4H), 4.48-4.58 (m, J=3.85 Hz, 1H), 5.01(s, 2H), 6.69-6.74 (m, 1 H), 6.75-6.80 (m, J=3.85 Hz, 1H), 7.11 (s, 1H),7.23-7.38 (m, 5H).

Example 143

To a 0° C. solution of Example 124 Part C compound (0.110 g; 0.458 mmol)in THF (2.29 mL) were added 2-phenylethanol (0.121 mL; 1.01 mmol) andPh₃P (0.265 g; 1.01 mmol), followed by the slow addition of DIAD (0.195mL; 1.01 mmol). The reaction mixture was stirred at 25° C. for 16 hunder Ar, then was diluted with water and extracted with EtOAc (3×). Thecombined organic extracts were washed with 1N aqueous NaOH and brine,dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 10-15-20% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.127 g;81%).

To a solution of Part A compound (0.127 g; 0.370 mmol) in THF (1.42 mL)and water (0.45 mL) was added LiOH.H₂O (0.017 g; 0.407 mmol). Thereaction mixture was stirred at 45° C. for 2 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give Part B compound (0.112 g;91%).

To a solution of Example 13 Part E compound (0.027 g; 0.109 mmol) in DMF(0.35 mL) were added HOAT (0.014 g; 0.104 mmol), Part B compound (0.030g; 0.091 mmol), DIPEA (0.018 mL; 0.104 mmol), and, lastly, EDCI (0.020g; 0.104 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (24.5 mg; 48%) as a clear,colorless oil. [M+H]⁺=563.2; ¹H NMR (400 MHz, CDCl₃): δ 1.16-1.28 (m,6H), 3.02 (t, J=6.60 Hz, 2H), 3.20 (s, 1H), 3.25 (s, 1H), 3.33 (s, 3H),3.41-3.54 (m, 2 H), 3.96-4.08 (m, 4H), 4.16 (t, J=6.87 Hz, 2H),4.57-4.67 (m, 1H), 6.63-6.69 (m, 1H), 6.83-6.89 (m, J=3.85 Hz, 1H),7.13-7.28 (m, 7H).

Example 144

To a solution of Example 13 Part E compound (0.100 g; 0.400 mmol) in DMF(2.0 mL) were added HOAT (0.052 g; 0.383 mmol), 3-isopropoxybenzoic acid(0.060 g; 0.333 mmol), DIPEA (0.07 mL; 0.383 mmol), and, lastly, EDCI(0.073 g; 0.383 mmol). The reaction mixture was stirred at 25° C. for 16h. Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with 0.5N aqueous HCl and brine,dried (MgSO₄), and concentrated in vacuo. The residue was purified bypreparative HPLC(YMC reverse phase ODS-5 u 30×100 mm column; flowrate=40 mL/min, 25 to 100% solvent B over 12 min, where solventA=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1 CH₃CN:H₂O:TFA) to givethe title compound (9.4 mg; 7%) as a clear, colorless oil. [M+H]⁺=413.1;¹H NMR (400 MHz, CDCl₃): δ 1.21-1.34 (m, J=7.15, 7.15 Hz, 12 H), 3.26(s, 1H), 3.31 (s, 1H), 4.00-4.14 (m, 4H), 4.68-4.80 (m, 1H), 6.91-6.99(m, 1H), 7.04-7.12 (m, J=8.25 Hz, 1H), 7.31-7.41 (m, 1H), 7.62-7.72 (m,2H).

Example 145

To a solution of Example 13 Part E compound (0.027 g; 0.105 mmol) in DMF(0.34 mL) were added HOAT (0.013 g; 0.093 mmol), Example 33 Part A acid(0.030 g; 0.087 mmol), DIPEA (0.016 mL; 0.093 mmol), and, lastly, EDCI(0.018 g; 0.932 mmol). The reaction mixture was stirred at 25° C. for 16h. Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (35.2 mg; 70%) as a clear,colorless oil. [M+H]⁺=577.2; ¹H NMR (400 MHz, CDCl₃): δ 1.21-1.37 (m, 12H), 2.82-2.93 (m, J=14.02, 5.22 Hz, 1H), 2.99-3.09 (m, 1H), 3.32-3.48(m, 5H), 3.51-3.66 (m, 2H), 4.06-4.26 (m, 4H), 4.68-4.84 (m, 2H),6.68-6.77 (m, 1H), 6.96-7.07 (m, J=3.85 Hz, 1H), 7.13-7.41 (m, 7H),10.77 (s, 1H).

Example 146

To a 0° C. solution of Example 26 Part A compound (0.166 g; 0.515 mmol)in THF (2.60 mL) were added iPrOH (0.087 mL; 1.13 mmol) and Ph₃P (0.30g; 1.13 mmol), followed by the slow addition of DIAD (0.219 mL; 1.13mmol). The reaction mixture was stirred at 25° C. for 16 h under Ar,then was diluted with water and extracted with EtOAc (3×). The combinedorganic extracts were washed with 1N aqueous NaOH and brine, dried(MgSO₄), and concentrated in vacuo. The residue was chromatographed(SiO₂; stepwise gradient from 20-40% solvent B, where solvent A=hexanesand solvent B=EtOAc) to give Part A compound (0.258 g; >100%,contaminated with reduced DIAD).

To a solution of Part A compound (0.189 g; 0.515 mmol) in THF (3.22 mL)and water (0.62 mL) was added LiOH.H₂O (0.024 g; 0.567 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then cooled to RT. Volatiles were removed invacuo, and the remaining aqueous solution was acidified with 0.5Naqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc (3×).The combined organic extracts were washed with brine, dried (MgSO₄), andconcentrated in vacuo to give Part B compound (0.214 g; >100%,contaminated with reduced DIAD).

To a solution of Example 13 Part E compound (0.043 g; 0.17 mmol) in DMF(0.55 mL) were added HOAT (0.022 g; 0.164 mmol), Part B compound (0.050g; 0.143 mmol), DIPEA (0.029 mL; 0.164 mmol), and, lastly, EDCI (0.031g; 0.164 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (37.5 mg; 60%) as a clear,colorless oil. [M+H]⁺=583.1; ¹H NMR (400 MHz, CDCl₃): δ 1.17-1.38 (m, 12H), 3.04 (s, 3H), 3.27 (s, 1H), 3.32 (s, 1H), 3.99-4.14 (m, 4H),4.64-4.77 (m, 1H), 6.79-6.83 (m, 1H), 6.88-6.96 (m, J=3.30 Hz, 1H),7.07-7.15 (m, J=8.79 Hz, 2H), 7.30-7.36 (m, 1H), 7.47-7.54 (m, 1H),7.84-7.92 (m, J=8.79 Hz, 2H).

Example 147

To a 0° C. solution of Example 124 Part C compound (0.100 g; 0.416 mmol)in THF (2.08 mL) were added iPrOH (0.019 mL; 0.916 mmol) and Ph₃P (0.240g; 0.916 mmol), followed by the slow addition of DIAD (0.177 mL; 0.916mmol). The reaction mixture was stirred at 25° C. for 16 h under Ar,then was diluted with water and extracted with EtOAc (3×). The combinedorganic extracts were washed with 1N aqueous NaOH and brine, dried(MgSO₄), and concentrated in vacuo. The residue was chromatographed(SiO₂; stepwise gradient from 5-10% solvent B, where solvent A=hexanesand solvent B=EtOAc) to give Part A compound (82.2 mg; 70%).

To a solution of Part A compound (0.082 g; 0.291 mmol) in THF (1.82 mL)and water (0.45 mL) was added LiOH.H₂O (0.014 g; 0.32 mmol). Thereaction mixture was stirred at 45° C. for 3 h in a sealed vial, then anadditional equivalent of LiOH. The reaction mixture was stirred at 45°C. for 16 h, then was cooled to RT. Volatiles were removed in vacuo, andthe remaining aqueous solution was acidified with 0.5N aqueous HCl topH<2. The aqueous layer was back extracted with EtOAc (3×). The combinedorganic extracts were washed with brine, dried (MgSO₄), and concentratedin vacuo to give Part B compound (83.0 mg; 100%).

To a solution of Example 13 Part E compound (0.034 g; 0.134 mmol) in DMF(0.43 mL) were added HOAT (0.018 g; 0.129 mmol), Part B compound (0.030g; 0.112 mmol), DIPEA (0.023 mL; 0.129 mmol), and, lastly, EDCI (0.025g; 0.129 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (28.0 mg; 50%) as a clear,colorless oil. [M+H]⁺=501.0; ¹H NMR (400 MHz, CDCl₃): δ 1.20-1.30 (m, 15H), 3.22 (s, 1H), 3.27 (s, 1H), 3.34 (s, 3H), 3.42-3.56 (m, 2H),4.00-4.12 (m, 4 H), 4.56-4.70 (m, 2H), 6.64-6.69 (m, 1H), 6.88-6.95 (m,J=3.30 Hz, 1H), 7.21-7.28 (m, J=8.24 Hz, 2H).

Example 148

To a cold solution (0° C.) of 3,5-dihydroxy-methylbenzoate (1.00 g; 5.95mmol) in THF (29.8 mL) were added iPrOH (0.787 mL; 13.10 mmol) and Ph₃P(3.43 g; 13.10 mmol), followed by the slow addition of DIAD (2.58 mL;13.1 mmol). The reaction mixture was stirred at 25° C. for 16 h underAr, then was diluted with water and extracted with EtOAc (3×). Thecombined organic extracts were washed with 1N aqueous NaOH and brine,dried (MgSO₄), and concentrated in vacuo. The crude product waschromatographed (SiO₂; stepwise gradient from 10-20-30% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (1.27 g;85%).

To a solution of Part A compound (0.300 g; 1.19 mmol) in THF (7.44 mL)and water (1.45 mL) was added LiOH.H₂O (0.055 g; 1.31 mmol). Thereaction mixture was stirred at 45° C. for 3 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give Part B compound (0.290 g;100%).

To a solution of Example 13 Part E compound (0.167 g; 0.668 mmol) in DMF(2.14 mL) were added HOAT (0.087 g; 0.641 mmol), Part B compound (0.133g; 0.557 mmol), DIPEA (0.116 mL; 0.641 mmol), and, lastly, EDCI (0.123g; 0.668 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (95.1 mg; 36%) as a whitesolid. [M+H]⁺=471.5; ¹H NMR (400 MHz, CDCl₃): δ 1.24-1.37 (m, 18H), 3.27(s, 1H), 3.32 (s, 1H), 4.01-4.19 (m, 4H), 4.58-4.72 (m, 2H), 6.65 (s,1H), 6.92-7.00 (m, J=3.85 Hz, 1H), 7.21-7.27 (m, 2H).

Example 149

To a solution of methyl 3,5-dihydroxybenzoate (1.75 g; 10.41 mmol) inacetone (14 mL was added K₂CO₃ (2.88 g; 20.82 mmol) and nBu₄NI (384 mg;1.04 mmol), followed by dimethyl sulfate (985 μL; 10.41 mmol). Thereaction mixture was heated at reflux (˜65° C.) for 3 h, then was cooledto RT. The mixture was filtered, and the filtrate was concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from 0to 45% solvent B over 40 min, where solvent A=hexanes and solventB=EtOAc) to give Part A compound (0.74 g; 39%) as a white solid.

To a mixture of Part A compound (75 mg; 0.412 mmol), 4-fluorophenylmethyl sulfone (72 mg; 0.412 mmol) and K₂CO₃ (114 mg; 0.824 mmol) wasadded DMF (1.6 mL). The reaction mixture was heated at 120° C. for 5 h,then was cooled to RT. The mixture was partitioned between EtOAc (10 mL)and H₂O (10 mL). The organic phase was washed with brine (5 mL), dried(MgSO₄), and concentrated in vacuo. The residue was chromatographed(SiO₂; continuous gradient from 0 to 80% solvent B over 12 min, wheresolvent A=hexanes and solvent B=EtOAc) to give Part B compound (119 mg;86%) as a colorless syrup.

To a solution of Part B compound (118 mg; 0.351 mmol) in THF (0.47 mL),MeOH (0.47 mL), and H₂O (0.47 mL) was added LiOH.H₂O (44 mg; 1.053mmol). After 1 h of stirring, the mixture was partitioned between EtOAc(6 mL) and 0.5 N aqueous HCl (6 mL). The aqueous phase was extractedwith EtOAc (6 mL). The combined organic extracts were washed with brine(6 mL), dried (MgSO₄), and concentrated in vacuo to give Part C compound(94 mg; 83%) as a white solid.

To a solution of Example 13 Part E compound (0.038 g; 0.150 mmol) in DMF(0.48 mL) were added HOAT (0.020 g; 0.144 mmol), Part C compound (0.040g; 0.125 mmol), DIPEA (0.025 mL; 0.144 mmol), and, lastly, EDCI (0.028g; 0.144 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (27.6 mg; 40%) as a whitesolid. [M+H]⁺=555.4; ¹H NMR (400 MHz, CDCl₃): δ 1.20 (t, J=7.15 Hz, 6H),3.01 (s, 3H), 3.24 (s, 1H), 3.30 (s, 1H), 3.83 (s, 3H), 3.94-4.09 (m,4H), 6.73-6.87 (m, 2H), 7.08 (d, J=8.79 Hz, 2H), 7.22-7.28 (m, 1H),7.36-7.43 (m, 1H), 7.86 (d, J=8.79 Hz, 2H).

Example 150

To a 0° C. mixture of Example 149 Part A compound (100 mg; 0.549 mmol),R-(−)-1-methoxy-2-propanol (70 μL; 0.714 mmol), and polymer-bound PPh₃(0.47 g; 1.43 mmol) in THF (2 mL) was added dropwise a solution of DIAD(162 μL; 0.823 mmol) in THF (0.20 mL). The reaction was stirred at RTfor 18 h, then was filtered. The resin was rinsed with THF (2×4 mL), andthe combined filtrates were concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 0 to 45% solvent B over20 min, where solvent A=hexanes and solvent B=EtOAc) to give Part Acompound (78 mg; 56%) as a colorless oil.

To a solution of Part A compound (74 mg; 0.291 mmol) in THF (0.39 mL),MeOH (0.39 mL), and H₂O (0.39 mL) was added LiOH.H₂O (37 mg; 0.873mmol). The reaction was stirred for 1 h, then was partitioned betweenEtOAc (5 mL) and 0.5 N aqueous HCl (5 mL). The aqueous phase wasextracted with EtOAc (5 mL). The combined organic extracts were washedwith brine (5 mL), dried (MgSO₄), and concentrated in vacuo to give PartB compound (68 mg; 97%) as a colorless syrup

To a solution of Example 13 Part E compound (0.041 g; 0.164 mmol) in DMF(0.52 mL) were added HOAT (0.087 g; 0.641 mmol), Part B compound (0.033g; 0.137 mmol), and DIPEA (0.028 mL; 0.158 mmol), and, lastly, EDCI(0.030 g; 0.158 mmol). The reaction mixture was stirred at 25° C. for 16h. Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 μm30×100 mm column; flow rate=40 mL/min, 25 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (38.1 mg; 59%) as a clear,colorless oil. [M+H]⁺=473.4; ¹H NMR (400 MHz, CDCl₃): δ 1.20-1.30 (m,9H), 3.23 (s, 1H), 3.28 (s, 1H), 3.35 (s, 3H), 3.43-3.55 (m, 2H), 3.80(s, 3H), 4.01-4.12 (m, 4H), 4.60-4.72 (m, 1H), 6.66-6.72 (m, 1H),6.89-6.94 (m, J=3.30 Hz, 1 H), 7.21-7.25 (m, 1H), 7.25-7.29 (m, 1H).

Example 151

To a solution of methyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate (0.029 g;1.20 mmol) in THF (2.49 mL) and water (0.25 mL) was added LiOH.H₂O(0.100 g; 0.301 mmol). The reaction mixture was stirred at 45° C. for 3h in a sealed vial, then an additional equivalent of LiOH was added. Thereaction mixture was stirred at 45° C. for 16 h, then was cooled to RT.The solvent was removed in vacuo, and the remaining aqueous solution wasacidified with 0.5N aqueous HCl to pH<2. The aqueous layer wasre-extracted with EtOAc (3×). The combined organic extracts were washedwith brine, dried (MgSO₄), and concentrated in vacuo to give Part Acompound (0.0954 g; 99%).

To a solution of Example 13 Part E compound (0.029 g; 0.114 mmol) in DMF(0.476 mL) were added HOAT (0.015 g; 0.11 mmol), Part A compound (0.030g; 0.095 mmol), DIPEA (0.019 mL; 0.110 mmol), and, lastly, EDCI (0.021g; 0.110 mmol). The reaction mixture was stirred at 25° C. for 16 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 0 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (13.8 mg; 26%) as a whitelyophilate. [M+H]⁺=551.2; ¹H NMR (400 MHz, CDCl₃) δ 1.23 (t, J=7.15 Hz,6 H), 3.23 (s, 1H), 3.28 (s, 1H), 3.94-4.10 (m, 4H), 4.27-4.39 (m,J=7.88, 7.88, 7.88 Hz, 2H), 4.46-4.58 (m, J=8.06, 8.06, 8.06 Hz, 2H),6.81-6.86 (m, J=3.30 Hz, 1H), 6.93-6.98 (m, J=9.34 Hz, 1H), 7.12-7.18(m, J=9.34, 3.30 Hz, 1H), 7.69-7.75 (m, J=3.30 Hz, 1H).

Example 152

To Example 26 Part A compound (0.130 g; 0.403 mmol) were successivelyadded 2-methoxyethanol (0.046 g; 0.605 mmol) in toluene (2.02 mL) and asuspension of Example 97 Part B compound (0.248 g; 0.605 mmol) in CH₂Cl₂(1.1 mL). The reaction mixture was stirred for 16 h at 25° C., then wasdiluted with water and extracted with EtOAc (3×). The combined organicextracts were washed with 1N aqueous NaOH and brine, dried (MgSO₄), andconcentrated in vacuo. The residue was chromatographed (SiO₂; stepgradient from 50-60% solvent B, where solvent A=hexanes and solventB=EtOAc) to give Part A compound (0.157 g; 93%).

To a solution of Part A compound (0.157 g; 0.413 mmol) in THF (3.42 mL)and water (0.342 mL) was added LiOH.H₂O (0.020 g; 0.827 mmol). Thereaction mixture was stirred at 45° C. for 3 h in a sealed vial, thencooled to RT. Volatiles were removed in vacuo, and the remaining aqueoussolution was acidified with 0.5N aqueous HCl to pH<2. The aqueous layerwas re-extracted with EtOAc (3×). The combined organic extracts werewashed with brine, dried (MgSO₄), and concentrated in vacuo to give PartB compound (0.166 g; 100%).

To a solution of Example 13 Part E compound (0.033 g; 0.130 mmol) in DMF(0.542 mL) were added HOAT (0.017 g; 0.125 mmol), Part B compound (0.040g; 0.108 mmol), DIPEA (0.022 mL; 0.125 mmol), and, lastly, EDCI (0.024g; 0.125 mmol). The reaction mixture was stirred at 25° C. for 5 h.Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 μm30×100 mm column; flow rate=40 mL/min, 0 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (34.4 mg; 51%) as a whitelyophilate. [M+H]⁺=599.2; ¹H NMR (400 MHz, CDCl₃): δ 1.25 (t, J=6.87 Hz,6 H), 3.00 (s, 3H), 3.24 (s, 1H), 3.29 (s, 1H), 3.39 (s, 3H), 3.67-3.77(m, 2H), 4.00-4.15 (m, 4H), 4.18-4.28 (m, 2H), 6.86-6.93 (m, 1H),6.94-7.00 (m, J=3.30 Hz, 1 H), 7.04-7.12 (m, J=8.79 Hz, 2H), 7.38-7.45(m, 1H), 7.58-7.64 (m, 1H), 7.81-7.88 (m, J=8.79 Hz, 2H).

Example 153

To methyl-3,5-dihydroxybenzoate (0.100 g; 0.595 mmol) were added(R)-1-methoxy-propan-2-ol (0.134 g; 1.487 mmol in toluene (2.97 mL),followed by a suspension of Example 97 Part B compound (0.610 g; 1.487mmol) in CH₂Cl₂ (2.72 mL). The reaction mixture was stirred for 2 daysat 25° C., then at 45° C. for 2 days, then was cooled to RT. Thereaction mixture was diluted with water and extracted with EtOAc (3×).The combined organic extracts were washed with 1N aqueous NaOH andbrine, dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; stepwise gradient from 10-20% solvent B, wheresolvent A=hexanes and solvent B=EtOAc) to give Part A compound (0.080 g;40%).

To a solution of Part A compound (0.080 g; 0.257 mmol) in THF (2.13 mL)and water (0.213 mL) was added LiOH.H₂O (0.012 g; 0.514 mmol). Thereaction mixture was stirred at 45° C. for 3 h in a sealed vial, then anadditional equivalent of LiOH was added. The reaction mixture wasstirred at 45° C. for 16 h, then was cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give Part B compound (0.082 g;100%).

To a solution of Example 13 Part E compound (0.036 g; 0.142 mmol) in DMF(0.592 mL) were added HOAT (0.019 g; 0.136 mmol), Part B compound (0.035g; 0.118 mmol), and DIPEA (0.024 mL; 0.136 mmol) and, lastly, EDCI(0.026 g; 0.136 mmol). The reaction mixture was stirred at 25° C. for 15h. Water was added, and the mixture was extracted with EtOAc (3×). Thecombined organic extracts were washed with sat. aqueous NH₄Cl, sat.aqueous NaHCO₃, and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-5 u30×100 mm column; flow rate=40 mL/min, 0 to 100% solvent B over 12 min,where solvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1CH₃CN:H₂O:TFA) to give the title compound (28.2 mg; 45%) as a clear,colorless oil. [M+H]⁺=531.3; ¹H NMR (400 MHz, CDCl₃) δ 1.22-1.29 (m,J=6.87, 6.87 Hz, 12H), 3.28 (s, 1H), 3.32-3.38 (m, 7H), 3.44-3.56 (m,4H), 4.06-4.16 (m, 4H), 4.64-4.73 (m, 2H), 6.70-6.76 (m, 1H), 6.94-7.00(m, J=3.85 Hz, 1H), 7.32-7.35 (m, J=2.20 Hz, 2H).

Example 154

To a solution of Example 134 compound (0.298 g; 0.560 mmol) in iPrOH(12.43 mL) and water (6.22 mL) was added oxone (0.791 g; 1.287 mmol).The reaction mixture was stirred for 16 h at 25° C., then was filteredand extracted with EtOAc. The combined filtrates were washed with waterand brine, dried (MgSO₄), and concentrated in vacuo to give Part Acompound (0.206 g; 38%).

15

To a solution of Part A compound (0.070 g; 0.125 mmol) in THF (1.03 mL)and water (0.103 mL) was added LiOH.H₂O (0.006 g; 0.249 mmol). Thereaction mixture was stirred at 45° C. for 1 h in a sealed vial, thentwo more equivalents of LiOH.H₂O were added. The reaction mixture wasstirred at 45° C. for 20 minutes, then cooled to RT. Volatiles wereremoved in vacuo, and the remaining aqueous solution was acidified with0.5N aqueous HCl to pH<2. The aqueous layer was re-extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated in vacuo to give Part B compound (0.082 g;87%).

To a 0° C. solution of the Part B compound (0.020 g; 0.044 mmol) in NMP(0.146 mL) was added 1M LiHMDS in THF (0.087 mL; 0.087 mmol). After 15min, 2-bromo-1-phenylethanone (0.017 g; 0.087 mmol) was added. Thereaction mixture was allowed to warm to RT and stirred at RT for 15 h,then was partitioned between sat. aqueous NH₄Cl and EtOAc. The organiclayer was washed with water (2×) and brine, dried (MgSO₄), andconcentrated in vacuo. The residue was purified by preparative HPLC(YMCreverse phase ODS-5 u 30×100 mm column; flow rate=40 mL/min, 0 to 100%solvent B over 12 min, where solvent A=90:10:0.1 H₂O:CH₃CN:TFA andsolvent B=90:10:0.1 CH₃CN:H₂O:TFA) to give the title compound (6.0 mg;24%) as a yellow oil. [M+H]⁺=577.3; ¹H NMR (400 MHz, CDCl₃) δ 1.05-1.12(m, J=6.05 Hz, 3H), 1.24 (t, 6H), 3.06 (s, 1H), 3.11 (s, 1H), 3.23-3.35(m, 4H), 3.36-3.42 (m, 1H), 3.93-4.10 (m, 4H), 4.24-4.35 (m, 1H),5.92-5.99 (m, J=4.40 Hz, 2H), 6.41-6.48 (m, 1H), 6.50-6.57 (m, 1H), 7.11(s, 1 H), 7.19 (s, 1H), 7.44-7.54 (m, J=7.70 Hz, 2H), 7.56-7.66 (m,J=7.15 Hz, 1H), 7.99-8.08 (m, J=8.25 Hz, 2H).

Example 155

To a 0° C. solution of Example 137 compound (0.021 g; 0.036 mmol) inanhydrous CH₂Cl₂ (0.369 mL) was added DAST (0.005 mL; 0.036 mmol). Thereaction mixture was stirred for 2 h at 0° C., followed by carefuladdition of sat. aqueous NaHCO₃ and stirred for 5 min, then waspartitioned between sat. aqueous NaHCO₃ and CH₂Cl₂. The aqueous layerwas re-extracted with CH₂Cl₂ (3×). The combined organic extracts werewashed with brine, dried (MgSO₄), and concentrated in vacuo. The residuewas purified twice by preparative HPLC(YMC reverse phase ODS-5 u 30×100mm column; flow rate=40 mL/min, 20 to 100% solvent B over 12 min, wheresolvent A=90:10:0.1 H₂O:CH₃CN:TFA and solvent B=90:10:0.1 CH₃CN:H₂O:TFA)to give the title compound (6.0 mg; 29%) as a clear, colorless oil.[M+H]⁺=565.2; ¹H NMR (400 MHz, CDCl₃) δ 1.22-1.32 (m, 12H), 2.75-2.87(m, J=13.74, 5.50 Hz, 2H), 2.92-3.03 (m, J=13.74, 6.60 Hz, 1H), 3.29 (s,1H), 3.34 (s, 1H), 4.06-4.17 (m, 4H), 4.33-4.45 (m, 1H), 4.45-4.57 (m,1H), 4.63-4.74 (m, 1H), 4.74-4.87 (m, 1H), 6.64-6.69 (m, J=2.20, 2.20Hz, 1H), 6.94-7.00 (m, J=3.30 Hz, 1H), 7.12-7.24 (m, 5H), 7.30 (s, 1H),7.33 (s, 1H).

Example 156

To a suspension of Example 97 Part B compound (1.4 g, 3.5 mmol) in DCM(6 mL) was added a solution of Example 26 Part A compound (141 mg, 0.44mmol) and (R)-(−)-3-hydroxytetrahydrofuran (0.081 mL, 1.00 mmol) intoluene (2 mL). The reaction was stirred at RT for 15 h, then wasdiluted with EtOAc (10 mL) and washed with water and brine. The organiclayer was dried (MgSO₄), and concentrated in vacuo. The residue waschromatographed (SiO₂; 40 g, 19 min continuous gradient, from 100%Hexane/0% EtOAc to 0% Hexanes/100% EtOAc) to provide Part A compound(254 mg, 148% yield, mixed with Ph₃PO) as a colorless oil.

To a solution of Part A compound (254 mg, 0.65 mmol) in THF (2 mL) wasadded 1N aqueous NaOH (1 mL, 1.00 mmol). The reaction was stirred at RTfor 15 h, then was diluted with EtOAc (6 mL) and acidified with 1Naqueous HCl (0.5 mL). The organic layer was washed with brine, dried(MgSO₄), and concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex Luna AXIA 30×100 mm column; flow rate=40mL/min, 30 to 100% solvent B over 10 min, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to give Part Bcompound (90 mg, 37% yield) as a colorless oil.

To a solution of Part B compound (25 mg, 0.066 mmol) in DMF (1 mL) wereadded Example 60 Part D2 amine (26.8 mg, 0.13 mmol), EDCI (25.3 mg, 0.13mmol), HOBT (20.2 mg, 0.13 mmol), and DIPEA (0.035 mL, 0.20 mmol). Thereaction was stirred at RT for 24 h. The reaction was purified directlyby preparative HPLC (Phenomenex Luna AXIA 30×100 mm column; flow rate=40mL/min, 30 to 100% solvent B over 10 min, where solvent A=90:10:0.1H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA) to provide the titlecompound (24.6 mg, 66% yield) as a white solid. [M+H]⁺=564.3; ¹H NMR(500 MHz, CDCl₃) δ 9.63 (1H, s), 7.92 (2H, d, J=8.80 Hz), 7.52 (1H, d,J=2.20 Hz), 7.33 (1H, s), 7.27 (1H, s), 7.09-7.18 (2H, m), 7.01 (1H, d,J=2.20 Hz), 6.71-6.86 (1H, m), 5.01-5.14 (1H, m), 4.37-4.60 (2H, m),4.07-4.22 (2H, m), 3.96-4.05 (3H, m), 3.84-3.96 (1H, m), 3.07 (3H, s),2.05-2.38 (2H, m), 1.55 (3H, d, J=14.85 Hz), 1.34 (3H, t, J=7.15 Hz).

Example 157

The title compound (27.4 mg, 73.6% yield; white solid) was synthesizedfrom Example 60 Part D1 amine using the procedure employed in Example156. [M+H]⁺=564.3; ¹H NMR (500 MHz, CDCl₃) δ 9.58 (1H, s), 7.92 (2H, d,J=8.25 Hz), 7.52 (1H, s), 7.31 (1H, s), 7.26 (1H, s), 7.14 (2H, d,J=8.25 Hz), 7.01 (1H, s), 6.80 (1H, s), 5.01-5.13 (1H, m), 4.41-4.60(2H, m), 4.06-4.21 (2H, m), 3.96-4.05 (3 H, m), 3.86-3.96 (1H, m), 3.07(3H, s), 2.09-2.35 (2H, m), 1.55 (3H, d, J=14.30 Hz), 1.27-1.39 (3H, m).

Example 158

To a RT solution of Example 26 Part A compound (117.8 mg, 0.365 mmol) inNMP (1.8 mL) under Ar was added Cs₂CO₃ (357 mg, 1.096 mmol), followed bydropwise addition of 2,2,2-trifluoroethyl methanesulfonate (0.075 mL,0.640 mmol). The mixture was stirred at 60° C. for 18 h, after whichmore 2,2,2-trifluoroethyl methanesulfonate (0.043 mL, 0.365 mmol) wasadded. The reaction was heated to 80° C. for 29 h, then was cooled toRT. The reaction was diluted with water and stirred for 1 h, then waspartitioned between EtOAc and saturated aqueous NaHCO₃. The organiclayer was washed with water (2×), and the combined aqueous layers wereback extracted with EtOAc. The combined organic extracts were washedwith brine, dried (Na₂SO₄), and concentrated in vacuo. The residue waschromatographed (12 g SiO₂, eluting from 0-10% EtOAc: CH₂Cl₂, thenflushing with 90% EtOAc) to give Part A compound (44 mg, 29%) as acolorless oil.

To a RT solution of Part A ester (44 mg, 0.109 mmol) in THF (0.8 mL) andMeOH (0.4 mL) under Ar was added 4N aqueous LiOH.H₂O (0.2 mL, 0.800mmol). A precipitate formed immediately, and the reaction was stirred atRT for 6.5 h, then was diluted with MeOH, and volatiles were removed invacuo. The residue was dissolved in water and acidified with 1N aqueousHCl. The aqueous layer was extracted with EtOAc; the organic layer waswashed with brine, dried (Na₂SO₄), and concentrated in vacuo to givePart B acid (38.6 mg, 91%) as a colorless solid.

To a RT suspension of Part B acid (20 mg, 0.051 mmol) in CH₂Cl₂ (0.3 mL)under Ar were added HATU (36 mg, 0.095 mmol), and a solution of Example13 Part E compound (18.6 mg, 0.074 mmol) in CH₂Cl₂ (0.3 mL), followed byDIPEA (0.036 mL, 0.205 mmol). The reaction was stirred at RT for 42 h,then EtOAc and sat. aqueous NaHCO₃ were added. The reaction was stirredfor 1 h, then was partitioned between EtOAc and sat. aqueous NaHCO₃. Theorganic layer was washed with sat. aqueous NaHCO₃, brine, dried(Na₂SO₄), and concentrated in vacuo. The residue was purified bypreparative HPLC (Phenomenex Luna 5 μm 21.2×100 mm column, detection at220 nm; flow rate=20 mL/min; continuous gradient from 50% A to 100% Bover 10 min+2 min hold time at 100% B, where A=90:10:0.1 H₂O:MeOH:TFAand B=90:10:0.1 MeOH:H₂O:TFA) to give one clean fraction. The desiredfraction was passed through a MeOH treated cartridge of Polymer LabStratoSpheres™ SPE PL-HCO₃ MP SPE resin (500 mg), washing well withMeOH. The filtrate was concentrated in vacuo, then azeotroped severaltimes with MeOH. The residue was taken up in CH₂Cl₂/MeOH; solids werefiltered off, and the filtrate was concentrated in vacuo to give thetitle compound (14.8 mg, 46%) as a tan colored solid. [M+H]⁺=623.2; ¹HNMR (400 MHz, CDCl₃) δ 1.24 (t, J=7.15 Hz, 6H), 3.09 (s, 3H), 3.46 (d,J=21.5 Hz, 2H), 3.99-4.10 (m, 4H), 4.48 (q, J=7.70 Hz, 2H), 6.83 (d,J=3.30 Hz, 1H), 6.92 (s, 1H), 7.16 (d, J=8.79 Hz, 2H), 7.46 (s, 1H),7.58 (s, 1 H), 7.95 (d, J=8.79 Hz, 2H), ¹⁹F NMR (400 MHz, CDCl₃):6-73.66.

Example 159

The title compound (20 mg, 51% yield, yellow oil) was prepared employingthe same general sequence as described in the synthesis of Example 74.[M+H]⁺=485.18; ¹H NMR (400 MHz, CDCl₃) δ ppm 6.94 (1H, d, J=3.95 Hz),6.52 (2H, d, J=2.20 Hz), 6.35 (1H, t, J=2.20 Hz), 4.49-4.57 (2H, m),4.10-4.19 (4 H, m), 3.78 (2H, s), 3.25-3.34 (2H, m), 1.27-1.36 (18H, m).

Example 160

The title compound (15 mg, 45% yield, yellow oil) was prepared employingthe same general sequence as described in the synthesis of Example 74.[M+H]⁺=485.18; ¹H NMR (400 MHz, CDCl₃) δ 7.12 (1H, d, J=8.79 Hz), 6.88(1 H, d, J=3.95 Hz), 6.41-6.46 (2H, m), 4.47-4.57 (1H, m), 4.07-4.17(4H, m), 3.75 (2H, s), 3.24-3.34 (2H, m), 1.23-1.37 (18H, m).

Example 161

A solution of methyl 3,5-dihydroxybenzoate (2.5 g, 14.9 mmol),1-fluoro-4-(methylsulfonyl)benzene (5.18 g, 29.8 mmol), and anhydrousK₂CO₃ (8.23 g, 59.6 mmol) in dry DMF (100 mL) was heated at 120′C for 10h, then was cooled to RT and filtered. The solid was washed with CH₂Cl₂(100 mL), and the combined filtrate was concentrated in vacuo. Theresidue was chromatographed (SiO₂; 80 g; continuous gradient from 100%hexane to 100% EtOAc over 40 min) to provide Part A compound (6.1 g, 86%yield) as a white solid. [M+H]⁺=477.

A solution of Part A compound (2.3 g, 4.83 mmol), and LiOH.H₂O (4.1 g,97.5 mmol) in THF (10 mL)/H₂O (5 mL) was stirred for 2 h at RT. Thereaction was acidified to pH 1 with 1N aqueous HCl, and extracted withEtOAc (3×15 mL). The combined organic extracts were washed with brine(30 mL), dried (MgSO₄) and concentrated in vacuo to give Part B compound(2.2 g, 99% yield) as a white solid. [M−H]=461.

To a suspension of the Part B compound (50 mg, 0.11 mmol) in CH₂Cl₂ (3mL) were added Example 13 Part E compound (27 mg, 0.11 mmol), Et₃N (30μL, 0.22 mmol), and BOP (72 mg, 0.16 mmol). The reaction was stirred for16 h, then was diluted with H₂O (1 mL), and extracted with CH₂Cl₂ (3×5mL). The combined organic extracts were washed with brine (3 mL), dried(MgSO₄), and concentrated in vacuo. The residue was purified bypreparative HPLC (YMC reverse phase ODS-A-5 μm 30×250 mm column; flowrate=25 mL/min, 20 to 100% solvent B over 30 min, hold to 40 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to afford the title compound (50 mg, 65% yield) as a white solid.[M+H]⁺=695; ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J=8.8 Hz, 4H), 7.65 (d,J=2.2 Hz, 2H), 7.20 (d, J=8.8 Hz, 4H), 7.09 (t, J=2.2 Hz, 1H), 7.01 (d,J=3.3 Hz, 1H), 4.11 (m, 4H), 3.28 (d, J=22.0 Hz, 2H), 3.06 (s, 6H), 1.28(t, J=6.9 Hz, 6H).

Example 162

A solution of methyl 3-bromo-5-hydroxybenzoate (2.13 g, 9.21 mmol),1-fluoro-4-(methylsulfonyl)benzene (1.93 g, 11.1 mmol), and anhydrousK₂CO₃ (2.55 g, 18.42 mmol) in dry DMF (15 mL) was heated at 120′C for 20h, then was cooled to RT and filtered. The solids were washed withCH₂Cl₂ (100 mL), and the combined filtrates were concentrated in vacuo.The residue was chromatographed (SiO₂; 80 g; continuous gradient from100% hexane to 100% EtOAc over 40 min) to provide Part A compound (1.64g, 48% yield) as a white solid. [M−H]=370.

A RT solution of Part A compound (124 mg, 0.322 mmol),2-fluoropyridin-4-ylboronic acid (54.4 mg, 0.386 mmol), K₂CO₃ (89 mg,0.644 mmol), and (PPh₃)₄Pd (18.6 mg, 16 mmol) in DME (4 mL) and water (1mL) was stirred under a stream of N₂ for 5 min. The mixture was thensealed and heated in an Emrys Optimizer® at 150° C. for 30 min. Thereaction was cooled to RT and was acidified to pH 2 with 1N aqueous HCl.The mixture was partitioned between EtOAc (3 mL) and water (3 mL), andwas extracted with EtOAc (3×10 mL). The combined organic extracts weredried (MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC(YMC reverse phase ODS-A-5 μm 30×250 mm column; flowrate=25 mL/min, 20 to 100% solvent B over 30 min, then held for 10 min,where solvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1MeOH:H₂O:TFA) to afford the Part B compound (80 mg, 64%) as a whitesolid. [M−H]=386.

To a suspension of the Part B compound (20 mg, 0.052 mmol) in CH₂Cl₂ (2mL) were added Example 13 Part E compound (13 mg, 0.052 mmol), Et₃N (11μL, 0.077 mmol), and BOP (27.4 mg, 0.062 mmol). The reaction was stirredfor 16 h, then was diluted with H₂O (1 mL) and extracted with CH₂Cl₂(3×5 mL). The combined organic extracts were washed with brine (3 mL),dried (MgSO₄) and concentrated in vacuo. The residue was purified bypreparative HPLC(YMC reverse phase ODS-A-5 μm 30×250 mm column; flowrate=25 mL/min, 20 to 100% solvent B over 30 min, hold to 40 min, wheresolvent A=90:10:0.1 H₂O:MeOH:TFA and solvent B=90:10:0.1 MeOH:H₂O:TFA)to afford the title compound (27 mg, 84% yield) as a white solid.[M+H]⁺=620; ¹H NMR (500 MHz, CD₃OD): δ 8.32-8.29 (m, 2H), 8.0 (d, J=8.8Hz, 2H), 7.85-7.82 (m, 2H), 7.72-7.69 (m, 1H), 7.51 (s, 1H), 7.30 (d,J=8.8 Hz, 2H), 7.00 (d, J=3.8 Hz, 1H), 4.12-4.05 (m, 4H), 3.37 (d,J=21.4 Hz, 2H), 3.13 (s, 3H), 1.28 (t, J=6.8 Hz, 6H).

Example 163

A solution of methyl 3-hydroxy-5-isopropoxybenzoate (Bioorg. Med. Chem.Lett. 2005, 15:2103) (609 mg, 2.90 mmol), methyl5-chloropyrazine-2-carboxylate (500 mg, 2.90 mmol), and K₂CO₃ (1.20 mg,8.69 mmol) in CH₃CN (20 mL) was heated to 80° C. for 2 h under Ar. Thereaction was cooled to RT, diluted with CH₂Cl₂ (50 mL), filtered and thefiltrate was concentrated in vacuo. The residue was chromatographed(SiO₂; 40 g; continuous gradient from 100% hexane to 100% EtOAc over 40min) to provide Part A compound (1.005 g, 100% yield) as a colorlessoil. [M+H]⁺=347.

A mixture of Part B compound (1.005 g, 2.9 mmol), azetidinehydrochloride (326 mg, 3.48 mmol), Et₃N (0.485 mL, 3.48 mmol), and MgCl₂(332 mg, 3.48 mmol) was stirred at RT for 5 h. More azetidinehydrochloride (326 mg, 3.48 mmol), Et₃N (0.485 mL, 3.48 mmol), and MgCl₂(332 mg, 3.48 mmol) were added. The reaction was stirred at RT for 30min, then was stored at 0° C. overnight, then diluted with CH₂Cl₂ (50mL), filtered, and the filtrate was concentrated in vacuo. The residuewas chromatographed (SiO₂; 40 g; continuous gradient from 100% hexane to100% EtOAc over 40 min) to provide Part B compound (267 mg, 25% yield)as a colorless oil. [M+H]⁺=372.

A solution of Part B compound (267 mg, 0.72 mmol) and LiOH.H₂O (90 mg,2.16 mmol) in THF (4 mL)/H₂O (4 mL) was stirred for 5 h at RT. Thereaction was acidified to pH 2 with 1N aqueous HCl, then was extractedwith EtOAc (3×10 mL). The combined organic extracts were washed withbrine (10 mL), dried (MgSO₄) and concentrated in vacuo to give Part Ccompound (200 mg, 78% yield) as a white solid. [M+H]⁺=358.

To a suspension of the Part C compound (14 mg, 0.039 mmol) in CH₂Cl₂(1.5 mL) were added Example 32 Part A compound (9.1 mg, 0.039 mmol),Et₃N (11 μL, 0.078 mmol), and BOP (34.7 mg, 0.078 mmol). The reactionwas stirred for 16 h at RT, then was diluted with H₂O (1 mL) andextracted with CH₂Cl₂ (3×5 mL). The combined organic extracts werewashed with brine (3 mL), dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by preparative HPLC(YMC reverse phase ODS-A-5 u30×250 mm column; flow rate=25 mL/min, 20 to 100% solvent B over 30 min,hold to 40 min, where solvent A=90:10:0.1 H₂O:MeOH:TFA and solventB=90:10:0.1 MeOH:H₂O:TFA) to afford the title compound (9.5 mg, 43%yield) as a white solid. [M+H]⁺=573; ¹H NMR (500 MHz, CDCl₃): δ 9.11 (s,1H), 8.84 (s, 1H), 8.33 (s, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 7.27 (s,1H), 6.95 (d, J=2.2 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 4.70-7.62 (m, 3H),4.44 (d, J=8.0 Hz, 2H), 4.26 (t, J=7.7 Hz, 2H), 4.15-4.05 (m, 4H),2.41-2.34 (m, 2H), 1.35 (d, J=6.1 Hz, 6H), 1.29 (t, J=7.2 Hz, 6H).

Example 164

To a −70° C. solution of LDA (2.9 mL, 5.79 mmol, 2N in THF) and DMPU(1.75 mL, 5.79 mmoL) in THF (5.1 mL) was slowly added methyl2-(4-(methylsulfonyl)phenyl)acetate (1.27 g, 5.55 mmol) (see WO00/58293), keeping the temperature below −65° C. The reaction wasstirred at −70° C. for 1 h and 4-(iodomethyl)cyclopent-1-ene (1.38 g,6.58 mmol) was added, keeping the temperature below −60° C. The reactionmixture was stirred at −70° C. for 30 min and then was warmed to RT andwas stirred for 18 h. The reaction was cooled in an ice bath and wasquenched with sat. aqueous NH₄Cl (20 mL). Volatiles were removed invacuo, and the mixture was extracted with EtOAc (2×). The combinedorganic layer was washed with Brine, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was chromatographed (SiO₂) to givethe Part A compound (880 mg, 51% yield) as a white solid.

To a 0° C. solution of Part A compound (880 mg, 2.85 mmol) in MeOH (8mL) and THF (4 mL) was added 1N aqueous NaOH (6 mL). The reaction wasslowly warmed to RT and was stirred at RT for 18 h. Volatiles wereremoved in vacuo, and the reaction was diluted with water, acidifiedwith 2N aqueous HCl (5 mL), and extracted with EtOAc. The organic layerwas washed with brine, dried (MgSO₄), filtered, and concentrated invacuo to give the Part B compound (830 mg, 96% yield) as a white solid.

To a 0° C. solution of Part B compound (29.4 mg, 0.1 mmol) in CH₂Cl₂(0.5 mL) under Ar was added oxalyl chloride (0.065 mL, 0.13 mmol, 2M inCH₂Cl₂) and DMF (3 μL). The reaction was stirred at 0° C. for 1 h andwas then warmed to RT and was stirred for 2 h. Volatiles were removed invacuo. To a 0° C. solution of the acid chloride residue in CH₂Cl₂ (0.5mL) under Ar was added a solution of pyridine (32.3 μL, 0.4 mmol) inCH₂Cl₂ (0.25 mL), followed by the addition of Example 7 Part B compound(27 mg, 0.11 mmol). The reaction was a stirred at RT for 18 h and wasdirectly purified by column chromatography (SiO₂, O-10% MeOH: CH₂Cl₂).The desired product and the Part B acid co-eluted, so the mixture wasextracted with CH₂Cl₂. The organic layer was washed with 0.5 N aqueousHCl, water, sat. aqueous NaHCO₃, and brine. The organic layer was dried(MgSO₄), filtered, and concentrated in vacuo to give the title compound(29 mg, 56% yield) as an oil. [M+H]⁺=522.2.

Example 165

To a solution of Example 26 Part A compound (80 mg, 0.248 mmol) in DMF(1 mL), were added 2-chloropyridine (0.047 mL, 0.496 mmol) and K₂CO₃(103 mg, 0.745 mmol). The reaction mixture was stirred at 120° C. for 40h, then was cooled to RT and filtered. The filtrate was diluted withMeOH, then was purified by preparative HPLC (Phenomenex Luna AXIA 30×100mm column; detection at 220 nm; flow rate=40 mL/min.; continuousgradient from 80% A to 100% B over 10 min., where A=10% MeOH/90%H₂O/0.1% TFA and B=90% MeOH/10% H₂O/0.1% TFA) to give Part A compound(26 mg, 27%) as a white solid.

To a solution of Part A compound (26 mg, 0.067 mmol) in DMF (1 mL), wasadded Example 13 Part E compound (33.8 mg, 0.135 mmol), EDCI (25.9 mg,0.135 mmol), HOBT (20.66 mg, 0.135 mmol), and DIPEA (0.035 mL, 0.202mmol). The reaction mixture was stirred at RT for 2 days. The reactionmixture was purified directly by preparative HPLC (Phenomenex Luna AXIA30×100 mm column; detection at 220 nm; flow rate=40 mL/min.; continuousgradient from 70% A to 100% B over 10 min., where A=10% MeOH/90%H₂O/0.1% TFA and B=90% MeOH/10% H₂O/0.1% TFA) to give the title compound(11 mg, 26% yield) as a yellow oil. [M+H]⁺=618.3; ¹H NMR (500 MHz,CDCl₃): δ 8.24 (1H, d, J=4.95 Hz), 7.95 (2H, d, J=8.80 Hz), 7.78-7.84(2H, m), 7.71 (1H, s), 7.20-7.25 (3H, m), 7.13 (1H, dd, J=6.87, 4.67Hz), 7.07 (1H, d, J=8.25 Hz), 7.04 (1H, d, J=3.85 Hz), 4.10-4.21 (4H,m), 3.34 (2H, d, J=21.44 Hz), 3.07 (3H, s), 1.32 (6H, t, J=6.87 Hz).

Example 166

The title compound (5 mg, 24% yield, yellow oil) was prepared from2-chloropyrimidine following the same general procedure as used for thesynthesis of Example 165. [M+H]⁺=619.3; ¹H NMR (500 MHz, CDCl₃): δ 8.63(2H, d, J=4.95 Hz), 7.88-7.99 (3H, m), 7.78 (1H, s), 7.27-7.28 (1H, m),7.24 (2H, d, J=9.35 Hz), 7.15 (1H, t, J=4.95 Hz), 7.05 (1H, d, J=3.30Hz), 4.11-4.21 (4H, m), 3.34 (2H, d, J=21.44 Hz), 3.08 (3H, s), 1.32(6H, t, J=7.15 Hz).

Example 167

The title compound (11.5 mg, 30% yield, yellow solid) was prepared from2-chloropyrazine following the same general procedure as used for thesynthesis of Example 165. [M+H]⁺=619.3; ¹H NMR (500 MHz, CDCl₃): δ 8.54(1H, s), 8.37 (1H, d, J=2.75 Hz), 8.16 (1H, s), 7.96 (2H, d, J=8.80 Hz),7.89 (1H, s), 7.77 (1H, s), 7.25-7.27 (1H, m), 7.24 (2H, d, J=8.80 Hz),7.05 (1H, d, J=3.85 Hz), 4.10-4.21 (4H, m), 3.34 (2H, d, J=21.44 Hz),3.08 (3H, s), 1.32 (6H, t, J=6.87 Hz).

Example 168

To a solution of dimethyl 5-hydroxyisophthalate (198 mg, 0.942 mmol) inDMF (2 mL), was added 1-fluoro-4-(methylsulfonyl)benzene (197 mg, 1.130mmol) and K₂CO₃ (391 mg, 2.83 mmol). The reaction mixture was stirred at120° C. for 41 h, then was cooled to RT and filtered. The filtrate wasdiluted with MeOH, then was purified by preparative HPLC (PhenomenexLuna AXIA 30×100 mm column; detection at 220 nm; flow rate=40 mL/min.;continuous gradient from 80% A to 100% B over 10 min., where A=10%MeOH/90% H₂O/0.1% TFA and B=90% MeOH/10% H₂O/0.1% TFA) to provide Part Acompound (176 mg, 53% yield) as a white solid. [M+H]⁺=351.2.

To a solution of Part A compound (85 mg, 0.243 mmol) in CH₂Cl₂ (1.0 ml)was added oxalyl chloride (0.243 mL, 0.485 mmol) and DMF (5.64 μL, 0.073mmol). The mixture was stirred at RT for 1 h, then was concentrated invacuo. The crude acid chloride was taken up in THF (1.0 mL), andpyrrolidine (0.041 mL, 0.485 mmol) and pyridine (0.059 mL, 0.728 mmol)were added. The reaction mixture was stirred at RT for 3 h, then wasdiluted with EtOAc (10 mL), washed with H₂O and brine, dried (MgSO₄),and concentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex Luna AXIA 30×100 mm column; detection at 220 nm; flowrate=40 mL/min.; continuous gradient from 70% A to 100% B over 10 min.,where A=10% MeOH/90% H₂O/0.1% TFA and B=90% MeOH/10% H₂O/0.1% TFA) toprovide Part B compound (93 mg, 95% yield) as a colorless oil.[M+H]⁺=404.3.

To a solution of art B compound (8.5 mg, 0.021 mmol) in THF (1 mL), wasadded 1N aqueous NaOH (0.063 mL, 0.063 mmol). The reaction mixture wasstirred at RT for 15 h and was diluted with EtOAc (6 mL), acidified with1N aqueous HCl (0.050 mL), and separated. The organic layer was washedwith brine, dried (MgSO₄), and concentrated in vacuo to give crude PartC compound (10 mg) as a white solid, which was used in the next stepwithout further purification. [M+H]⁺=390.2.

To a solution of Part C compound (10 mg, 0.026 mmol) in DMF (1 mL), wasadded Example 13 Part E compound (12.9 mg, 0.051 mmol), EDCI (9.9 mg,0.051 mmol), HOBT (7.9 mg, 0.051 mmol), and DIPEA (0.013 mL, 0.077mmol). The reaction mixture was stirred at RT for 4 days, then waspurified directly by preparative HPLC (Phenomenex Luna AXIA 30×100 mmcolumn; detection at 220 nm; flow rate=40 mL/min.; continuous gradientfrom 70% A to 100% B over 10 min., where A=10% MeOH/90% H₂O/0.1% TFA andB=90% MeOH/10% H₂O/0.1% TFA) to provide the title compound (3 mg, 23%yield over 2 steps) as a white solid. [M+H]⁺=622.3; ¹H NMR (500 MHz,CDCl₃): δ 8.18 (1H, s), 7.89-8.00 (3H, m), 7.55 (1H, s), 7.19 (2H, d,J=8.80 Hz), 7.05 (1H, d, J=3.30 Hz), 4.05-4.23 (4H, m), 3.50-3.74 (4H,m), 3.35 (2H, d, J=21.44 Hz), 3.09 (3H, s), 1.85-2.04 (4H, m), 1.32 (6H,t, J=7.15 Hz).

Example 169

To a solution of Example 13 Part A compound (377 mg, 1.08 mmol) inCH₂Cl₂ (5 mL) at RT under Ar was added TMSBr (0.307 mL, 2.37 mmol).After stirring at RT for 15 h, the reaction mixture was concentrated invacuo under scrupulously dry conditions to provide Part A compound as acolorless oil, which was used in the next step without furtherpurification.

To a solution of Part A compound in dry CH₂Cl₂ (5 mL; protected from theatmosphere by a CaCl₂-filled drying tube) was added oxalyl chloride(0.207 mL, 2.37 mmol) and DMF (8 μL, 0.1 mmol). Considerable foaming wasobserved, eventually resulting in the formation of a beige precipitate.After stirring at RT for 3 h, the reaction mixture was concentrated invacuo and the residue was taken up in THF (12 mL) and cooled to −65° C.under Ar. To this slurry was added a solution of 1,3-propanediol (0.086mL, 1.18 mmol) in MeCN (6 mL) over 2 min and stirred for 5 min at −65°C. Pyridine (0.183 mL, 2.26 mmol) was then added over 1 min, and thereaction mixture was allowed to warm to RT and stirred for 16 h at RT.The mixture was partitioned between EtOAc and 5% aqueous NaHSO₄ (25 mLeach). The organic phase was dried (Na₂SO₄) and concentrated in vacuo.The residue was purified by preparative HPLC (Phenomenex Luna 21.2×100mm column; detection at 254 nm; flow rate=20 mL/min.; continuousgradient from 0% A to 100% B over 10 min, where A=10% MeCN/90% H₂O/0.1%TFA and B=90% MeCN/10% H₂O/0.1% TFA) to provide Part B compound (71 mg,20% yield) as a white amorphous solid. [M+H]⁺=335.

To a stirred solution of Part B compound (71 mg, 0.21 mmol) in dryCH₂Cl₂ (2 mL; protected from the atmosphere by a CaCl₂-filled dryingtube) at RT was added TFA (0.5 mL). The reaction was stirred for 4 h atRT, then was concentrated in vacuo. The residue was dissolved in MeOHand eluted through a StratoSpheres™ SPE PL-HCO₃ MP ion exchangecartridge (0.9 meq capacity) with MeOH. Concentration of the eluent invacuo provided Part C compound as a white amorphous solid (43 mg, 86%yield). [M+H]⁺=235.

To a stirred slurry of Example 26C compound (69 mg, 0.18 mmol) in CH₂Cl₂(2 mL) at RT under Ar were successively added HOAt (25 mg, 0.18 mmol)and EDC (35 mg, 0.18 mmol). A clear solution formed within 5 min. After30 min, this solution was added to a slurry of Part C compound in THF (2mL) at RT under Ar, followed by iPr₂NEt (0.016 mL, 0.43 mmol) and DMAP(2.6 mg, 0.02 mmol). After stirring for 18 h at RT, analytical HPLCindicated that no product had formed. The reaction mixture wasconcentrated in vacuo and taken up in dry MeCN (3 mL), then was heatedto reflux under Ar, whereupon a solution formed. After 2 h at reflux,analytical HPLC indicated that almost all the amine had been consumed.The reaction mixture was cooled to RT and concentrated in vacuo. Theresidue was partitioned between EtOAc and saturated aqueous NaHCO₃ (20mL each). The organic phase was washed with brine and aqueous 10%NaHSO₃, dried (Na₂SO₄) and concentrated in vacuo. Purification of theoily residue by preparative HPLC (Phenomenex Luna 21.2×100 mm column;detection at 220 nm; flow rate=20 mL/min.; continuous gradient from 0% Ato 100% B over 10 min., where A=10% MeCN/90% H₂O/0.1% TFA and B=90%MeCN/10% H₂O/0.1% TFA) provided the title compound (35 mg, 28% yield) asa white amorphous solid. [M+H]⁺=597. ¹H NMR (400 MHz, CDCl₃): δ 7.92(2H, d, J=7.1 Hz), 7.59 (1H, s), 7.42 (1H, s), 7.17 (2H, d, J=8.80 Hz),6.85 (2H, m), 4.73 (1H, m), 4.35 (2H, m), 4.12 (2H, m), 3.66-3.51 (3H,m), 3.41 (3H, s), 3.07 (3H, s), 1.92-1.72 (2H, m), 1.34 (3H, d, J=6.0Hz).

Assays for Glucokinase Activation

The compounds of formula I of the invention activate glucokinase. Assayswhich may be used in testing the compounds of formula I of the inventionin activating glucokinase are known in the art such as disclosed in U.S.Pat. Nos. 6,320,050, 6,384,200 and 6,610,846 and WO 2004/052869 and inCastellano, A. L., Dong, H., Fyfe, M. C. T., Gardner, L. S., Kamikozawa,Y. et al. (2005) “Glucokinase activating ureas”, Bioorg. Med. Chem.Letters, 15:1501-1504, and Grimsby, J., Sarabu, R., Corbett, W. L.,Haynes, N-E., Bizzarro, F. T., Coffey, J. W., Guertin, K. R., Hilliard,D. W., Kester, R. F., Mahaney, P. E., Marcus, L., Qi, L., Spence, C. L.,Tengi, J., Magnuson, M. A., Chu, C. A., Dvorozniak, M. T., Matschinsky,F. M., Grippo, J. F. (2003) “Allosteric Activators of Glucokinase:Potential Role in Diabetes Therapy”, Science, 301:370-373.

In general, compounds of the present invention, such as particularcompounds disclosed in the following examples, have been identified toenhance the activity of glucokinase at concentrations equivalent to, ormore potently than, 100 μM, preferably 10 μM, more preferably 1 μM,thereby demonstrating compounds of the present invention as especiallyeffective enhancers of activity of glucokinase. Potencies can becalculated and expressed as either EC₅₀ (concentration to achieve 50% offull activation) and/or the maximum percentage activation abovebackground, and refer to activity measured employing the assay systemdescribed above.

Assay and Biological Data

Compounds of formula I of the invention, including compounds describedin the Examples hereof, have been tested in the following assay and haveshown to be activators of glucokinase.

Glucokinase Tandem Enzymatic Assay

Enzymatic activity of human glucokinase (GK) was measured by incubatingGK, ATP, and glucose for discrete time periods followed by quenchingwith EDTA (ethylenediamine tetra-acetic acid). Relative amounts ofproduct glucose-6-phosphate (G6P) were measured by then running adetection assay using G6P dehydrogenase and measuring the conversion ofThioNAD (thio-nicotinamide adenine dinucleotide) to ThioNADH(thio-dihydronicotinamide adenine dinucleotide) at a wavelength of 405nm. This ‘uncoupled’ enzymatic reaction is denoted as the GK ‘tandem’assay. Activation of GK by compounds can be assessed using this assay.The GK tandem assay protocol described below was followed using a rangeof activator compound concentrations from 0 to 100 μM at 5 and 12 mM ofglucose. Human full-length glucokinase (GK, 15 nM) was incubated with 5or 12 mM glucose in a 384 well black microtiter plate with a clearbottom. To initiate the GK reaction, magnesium-ATP (3 mM finalconcentration) was added to GK in buffer (final buffer conditions of 25mM HEPES buffer, pH 7.1, containing 1 mM dithiothreitol and 5% DMSO).The total reaction volume was 20 μL. The reaction was allowed to proceedfor ten minutes and was then quenched with 5 μL EDTA; 45 mM final). Thecomponents of the detection reaction, ThioNAD and G6PDH(glucose-6-phosphate dehydrogenase) (final concentrations of 650 μM and3.33 Units, respectively), were then added together in a volume of 25μL, (to give a total volume of 50 μL). Absorbance measurements were madeat 405 nm on a Spectramax Plus 384 absorbance plate reader (MolecularDevices). Absorbance was read, background glucose-6-phosphate levelswere subtracted, after which activation was calculated as a percentageof control activity. Control activity was determined using GK in thepresence of vehicle (DMSO), with background glucose-6-phosphatesubtracted. Background glucose-6-phosphate was determined bypre-quenching GK with EDTA prior to reaction initiation with ATP.

Expression and Purification of Human GK

Full-length human hepatic GK (untagged) was expressed in BL21 STAR(DE3)pLysS cells (Invitrogen) at 25° C. as described by Mookhtiar et al.(1). The protein was purified essentially as described by Lange (2) witha slight modification. Briefly, cell pellets were lysed via three roundsof freezing and thawing, centrifuged at 15000 g for clarification, andprecipitated with 40-65% (NH4)2SO4. The resulting pellet was resuspendedin buffer, dialyzed, and applied directly to a Q-Sepharose (Sigma)column followed by elution with a linear 100-600 mM KCl gradient. GKcontaining fractions were pooled, dialyzed overnight vs. 25 mM Hepes pH7.2/1 mM MgCl2/1 mM EDTA/0.1 M KCl/1 mM DTT, then dialyzed again withsame buffer with 10% glycerol added.

REFERENCES

-   1. Mookhtiar, K. A., Kalinowski, S. S., Brown, K. S., Tsay, Y. H.,    Smith-Monroy, C., and Robinson, G. W. (1996) “Heterologous    expression and characterization of rat liver glucokinase regulatory    protein”, Diabetes, 45:1670-1677.-   2. Lange, A. J., Xu, L. Z., Van Poelwijk, F., Lin, K., Granner, D.    K., and Pilkis, S. J. (1991) “Expression and site-directed    mutagenesis of hepatic glucokinase”, Biochem. J., 277:159-163.

Biological data for select Examples are shown in the table below.

EC₅₀ (nM) with Human Glucokinase Example No. @ 12 mM Glucose 169 9 51 1582 18 137 21 50 22 122 23 145 24 33 26 37 34 163 38 54 49 32 65 29 98148 178 22 402 112 428 113 437 139 467 116 469 134 476 84 492 56 534 44564

For other Examples, the EC₅₀ values could not be calculated from theactivation curves, so the maximal activation data (expressed as a % ofbasal activation) for some select Examples are shown in the table below.

Maximal activation (%) Human Glucokinase Example No. @ 12 mM Glucose 121126% 65 162% 35 133% 79 133% 86 141% 123 135% 74 142% 23 150%

In Vivo Studies: Oral Glucose Tolerance Test (OGTT)

Oral glucose tolerance tests were carried out on male DIO (diet-inducedobese) C57BL/6J mice fed a high fat diet (60% kcal from fat) for 26weeks prior to experimentation. Mice were fasted overnight before usefor experiments. A test compound or vehicle (either: 1) 40% PEG 400+10%Cremophore+50% water or 2) 10% dimethyl acetamide+10% ethanol+10%Cremophore+70% water) was given orally 60 min before oral administrationof a glucose solution at a dose of 2 g/kg body weight (oral glucosetolerance test; OGTT). Blood glucose levels were measured from tail-bledsamples taken at different time points before and after administrationof glucose (time course of 2 hours). A time curve of the blood glucosewas generated and the change from baseline area-under-the curve (ΔAUC)from 0-120 min was calculated (the time glucose administration beingtime zero).

The examples in the table below reduced glucose AUC levels in an OGTTtest in DIO mice as described above.

Reduction in Glucose Example No. AUC at 30 mg/kg dose 37 88% 148 60% 14571% 54 68-82%   29 66-78%   44 62-80    32 79% @ 30 μmol/kg 82 44% @ 10μmol/kg

1. A compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein: R₄ is selected from the group consisting of: —(CH₂)_(n)—Z—(CH₂)_(m)—PO(OR₇)(OR₈), —(CH₂)_(n)Z—(CH₂)_(m)—PO(OR₇)R₉, and —(CH₂)_(n)Z—(CH₂)_(m)—PO—(R₉)R₁₀; R₇ and R₈ are the same or different and are independently selected from alkyl, or R₇ and R₈ can be cyclized into a ring

R₉ and R₁₀ are the same or different and are independently selected from the group consisting of alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; or R₉ and R₁₀ can be cyclized into a ring

or R₇ and R₉ can be cyclized into a ring

Z is a bond, O, S, SO₂, alkylene, or alkenylene wherein said alkylene or alkenylene may be optionally substituted with hydroxyl, alkoxy, aminoalkyl, aminoaralkyl, aminoheteroaralkyl, aminoaryl, aminoheteroaryl, or carboxy; m is zero, 1 or 2, provided that when Z is O, S or SO₂, m is 1 or 2; n is 1 or 2; R₅ and R₆ are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen and carboxy, or one or both of R₅ and R₆ is absent; X is a bond; Y is R₃—(CH₂)_(s)—; s=zero; and R₃ is phenyl substituted with zero to two substituent groups independently selected: (a) —OR^(a) wherein R^(a) is: (i) alkyl, wherein said alkyl may be further substituted with at least one of halo, alkoxy or phenyl; (ii) phenyl, optionally substituted with —SO₂R^(c) wherein R^(c) is alkyl; (iii) a 4 to 7 membered heterocyclo optionally substituted with —SO₂R^(c) wherein R^(c) is alkyl; (iv) pyridinyl or pyrazinyl, optionally substituted with —C(═O)NR^(d)R^(b) or —SO₂R^(c) wherein R^(d) and R^(b) may join together with the N to which they are attached to form a 4- to 7-membered heterocyclo and R^(c) is alkyl; and/or (b) —C(═O)R^(a) wherein R^(a) is a four to seven membered heterocyclo.
 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y—X—CO— is:


3. The compound according to claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.
 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R₄ is —(CH₂)_(n)Z—(CH₂)_(m)—PO(OR₇)R₉.
 5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R₄ is —(CH₂)_(n)Z—(CH₂)_(m)—PO—(R₉)R₁₀.
 6. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R₄ is —(CH₂)_(n)—Z—(CH₂)_(m)—PO(R₇)R₈).
 7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein: Z is a bond; m is zero; n is 1 or 2; R₇ is alkyl; and R₈ is alkyl.
 8. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R₄ is:


9. The compound according to claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.
 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R₄ is —(CH₂)_(n)Z—(CH₂)_(m)—PO(OR₇)R₉.
 11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R₄ is —(CH₂)_(n)Z—(CH₂)_(m)—PO—(R₉)R₁₀.
 12. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R₄ is —(CH₂)_(n)—Z—(CH₂)_(m)—PO(OR₇)(OR₈).
 13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: R₇ is alkyl; and R₈ is alkyl.
 14. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R₄ is:


15. The compound according to claim 1 having the structure:

or a pharmaceutically acceptable salt thereof, wherein: wherein R₄ is:

R^(a) is C₁₋₄alkyl.
 16. A pharmaceutical composition comprising a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; and optionally another therapeutic agent which is an anti-diabetic agent, anti-hyperglycemic agent, anti-hyperinsulinemic agent, anti-retinopathic agent, anti-neuropathic agent, anti-nephropathic agent, anti-atherosclerotic agent, anti-infective agent, anti-ischemic agent, anti-hypertensive agent, anti-obesity agent, anti-dyslipidemic agent, anti-hyperlipidemic agent, anti-hypertriglyceridemic agent, anti-hypercholesterolemic agent, anti-ischemic agent, anti-cancer agent, anti-cytotoxic agent, anti-restenotic agent, anti-pancreatic agent, lipid lowering agent, appetite suppressant, memory enhancing agent, or cognitive agent.
 17. A pharmaceutical combination comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and an additional antidiabetic agent selected from the group consisting of metformin, a sulfonylurea, a thiazolidinedione, an SGLT2 inhibitor, and a DPPIV inhibitor.
 18. The pharmaceutical combination according to claim 17, wherein said compound according to claim 1 is:

or a pharmaceutically acceptable salt thereof, wherein R₄ is:


19. A method for treating, preventing, or slowing the progression of a disease requiring glucokinase activator therapy wherein said disease is diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive impairment and dementia, bone disease, HIV protease associated lipodystrophy, or glaucoma, which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of a compound of formula I as defined in claim
 1. 20. The method of claim 16 wherein said method is a method for treating Type II diabetes, which comprises administering to a patient in need of treatment a compound as defined in claim
 1. 